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Critical Reviews™ in Immunology
Impact-faktor: 1.404 5-jähriger Impact-Faktor: 3.347 SJR: 0.706 SNIP: 0.55 CiteScore™: 2.19

ISSN Druckformat: 1040-8401
ISSN Online: 2162-6472

Volumes:
Volumen 40, 2020 Volumen 39, 2019 Volumen 38, 2018 Volumen 37, 2017 Volumen 36, 2016 Volumen 35, 2015 Volumen 34, 2014 Volumen 33, 2013 Volumen 32, 2012 Volumen 31, 2011 Volumen 30, 2010 Volumen 29, 2009 Volumen 28, 2008 Volumen 27, 2007 Volumen 26, 2006 Volumen 25, 2005 Volumen 24, 2004 Volumen 23, 2003 Volumen 22, 2002 Volumen 21, 2001 Volumen 20, 2000 Volumen 19, 1999 Volumen 18, 1998 Volumen 17, 1997 Volumen 16, 1996 Volumen 15, 1995 Volumen 14, 1994

Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.2020033391
pages 93-133

Multiple Defects of Natural Killer Cells in Cancer Patients: Anarchy, Dysregulated Systemic Immunity, and Immunosuppression in Metastatic Cancer

Anahid Jewett
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA
Janko Kos
Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Kawaljit Kaur
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA
Tamara Lah Turnsek
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
Barbara Breznik
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA; Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
Emanuela Senjor
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA; Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Paul Wong
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA
Kristin Y. Nguyen
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA
Meng-Wei Ko
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA

ABSTRAKT

We have previously demonstrated that natural killer (NK) cells are the main immune effectors that can mediate selection and differentiation of different cancer stem cells and undifferentiated tumors via lysis and secreted or membrane-bound interferon-γ and tumor necrosis factor-α, respectively. This leads to growth inhibition and tumor metastasis curtailment. In this review, we present an overview of our findings on NK cell biology and its significance in selection and differentiation of stem-like tumors using in vitro and in vivo studies conducted in nonobese diabetic/severe combined immunodeficiency (scid)/interleukin-Rγ--, humanized−bone-marrow/liver/thymus (hu-BLT) mice, and those of human cancer patients. Moreover, we present recent advances in NK cell expansion and therapeutic delivery and discuss the superiority of allogeneic supercharged NK cells over their autologous counterparts for cancer treatment. We review potential loss of NK cell numbers and function at neoplastic and preneoplastic stages of tumorigenesis as a potential mechanism for pancreatic cancer induction and progression. We believe that NK cells should be placed highly in the armamentarium of tumor immunotherapy due to their indispensable role in targeting cancer stem-like/poorly differentiated tumors and a variety of other key NK cell functions that are discussed in this report, including their role in CD8+ T-cell expansion and targeting gene knockout or dedifferentiated tumors. The combination of allogeneic supercharged NK cells and other immunotherapeutic strategies such as oncolytic viruses, antibody-dependent cellular cytotoxicity-inducing antibodies, checkpoint inhibitors, chimeric antigen receptor (CAR)-T cells and CAR-NK cells, chemotherapeutics, and radiotherapeutic strategies can be used for optimal eradication of tumors.

REFERENZEN

  1. Fang F, Xiao W, Tian Z. NK Cell-based immunotherapy for cancer. Semin Immunol. 2017;31:37-54. .

  2. Freud AG, Mundy-Bosse BL, Yu J, Caligiuri MA. The broad spectrum of human natural killer cell diversity. Immunity. 2017;47(5):820-33. .

  3. Lopez-Soto A, Gonzalez S, Smyth MJ, Galluzzi L. Control ofmetastasis by NK cells. Cancer Cell. 2017;32(2):135-54. .

  4. Kozlowska AK, Topchyan P, Kaur K, Tseng HC, Teruel A, Hiraga T, Jewett A. Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs. J Cancer. 2017;8(4):537-54. .

  5. Jewett A, Kos J, Fong Y, Ko MW, Safaei T, Perisic Nanut M, Kaur K. NK cells shape pancreatic and oral tumor microenvironments; role in inhibition of tumor growth and metastasis. Semin Cancer Biol. 2018;53:178-88. .

  6. Kaur K, Nanut MP, Ko MW, Safaie T, Kos J, Jewett A. Natural killer cells target and differentiate cancer stemlike cells/undifferentiated tumors: strategies to optimize their growth and expansion for effective cancer immunotherapy. Curr Opin Immunol. 2018;51:170-80. .

  7. Elliott JM, Yokoyama WM. Unifying concepts of MHC-dependent natural killer cell education. Trends Immunol. 2011;32(8):364-72. .

  8. Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, French AR, Sunwoo JB, Lemieux S, Hansen TH, Yokovama WM. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature. 2005;436(7051):709-13. .

  9. Mrozek E, Anderson P, Caligiuri MA. Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells. Blood. 1996;87(7):2632-40. .

  10. Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22(11):633-40. .

  11. Carrega P, Ferlazzo G. Natural killer cell distribution and trafficking in human tissues. Front Immunol. 2012;3:347. .

  12. Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH. Activating and inhibitory receptors of natural killer cells. Immunol Cell Biol. 2011;89(2):216-24. .

  13. Kim N, Lee HH, Lee HJ, Choi WS, Lee J, Kim HS. Natural killer cells as a promising therapeutic target for cancer immunotherapy. Arch Pharm Res. 2019;42(7):591-606. .

  14. Abel AM, Yang C, Thakar MS, Malarkannan S. Natural killer cells: development, maturation, and clinical utilization. Front Immunol. 2018;9:1869. .

  15. Perisic Nanut M, Sabotic J, Jewett A, Kos J. Cysteine cathepsins as regulators of the cytotoxicity of NK and T cells. Front Immunol. 2014;5:616. .

  16. Melsen JE, Lugthart G, Lankester AC, Schilham MW. Human circulating and tissue-resident CD56bright natural killer cell populations. Front Immunol. 2016;7:262. .

  17. Magister S, Tseng H-C, Bui VT, Kos J, Jewett A. Regulation of split anergy in natural killer cells by inhibition of cathepsins C and H and cystatin F. Oncotarget. 2015;6(26):22310-27. .

  18. Jewett A, Cacalano NA, Head C, Teruel A. Coengagement of CD16 and CD94 receptors mediates secretion of chemokines and induces apoptotic death of naive natural killer cells. Clin Cancer Res. 2006;12(7 Pt 1):1994-2003. .

  19. Tseng HC, Arasteh A, Paranjpe A, Teruel A, Yang W, Behel A, Alva JA, Walter G, Head C, Ishikawa TO, Herschman HR, Cacalano N, Pyle AD, Park NH, Jewett A. Increased lysis of stem cells but not their differentiated cells by natural killer cells; dedifferentiation or reprogramming activates NK cells. PLoS One. 2010;5(7):e11590. .

  20. Jewett A, Teruel A, Romero M, Head C, Cacalano N. Rapid and potent induction of cell death and loss of NK cell cytotoxicity against oral tumors by F(ab')2 fragment of anti-CD 16 antibody. Cancer Immunol Immunother. 2008;57(7):1053-66. .

  21. Tseng HC, Cacalano N, Jewett A. Split anergized natural killer cells halt inflammation by inducing stem cell differentiation, resistance to NK cell cytotoxicity and prevention of cytokine and chemokine secretion. Oncotarget. 2015;6(11):8947-59. .

  22. Schwartz RH. T Cell anergy. Ann Rev Immunol. 2003;21: 305-34. .

  23. Jewett A, Tseng HC. Tumor induced inactivation of natural killer cell cytotoxic function; implication in growth, expansion and differentiation of cancer stem cells. J Cancer. 2011;2:443-57. .

  24. Kaur K, Chang HH, Cook J, Eibl G, Jewett A. Suppression of gingival NK cells in precancerous and cancerous stages of pancreatic cancer in KC and BLT-humanized mice. Front Immunol. 2017;8:1606. .

  25. Kaur K, Cook J, Park SH, Topchyan P, Kozlowska A, Ohanian N, Fang C, Nishimura I, Jewett A. Novel strategy to expand super-charged NK cells with significant potential to lyse and differentiate cancer stem cells: differences in NK expansion and function between healthy and cancer patients. Front Immunol. 2017;8:297. .

  26. Kaur K, Chang HH, Topchyan P, Cook JM, Barkhordarian A, Eibl G, Jewett A. Deficiencies in natural killer cell numbers, expansion, and function at the pre-neoplastic stage of pancreatic cancer by KRAS mutation in the pancreas of obese mice. Front Immunol. 2018;9:1229. .

  27. Shurin MR, Umansky V, Malyguine A, Hurwitz AA, Apte RN, Whiteside T, Jewett A, Thanavala Y, Murphy WJ. Cellular and molecular pathways in the tumor immunoenvironment: 3rd cancer immunotherapy and immunomonitoring (CITIM) meeting, 22-25 April 2013, Krakow, Poland. Cancer Immunol Immunother. 2014;63(1):73-80. .

  28. Raulet DH, Guerra N. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol. 2009;9(8):568-80. .

  29. Lai P, Rabinowich H, Crowley-Nowick PA, Bell MC, Mantovani G, Whiteside TL. Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. Clin Cancer Res. 1996;2(1):161-73. .

  30. Kuss I, Saito T, Johnson JT, Whiteside TL. Clinical significance of decreased Z chain expression in peripheral blood lymphocytes of patients with head and neck cancer. Clin Cancer Res. 1999;5(2):329-34. .

  31. Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet. 2000;356(9244):1795-9. .

  32. Bucklein V, Adunka T, Mendler AN, Issels R, Subklewe M, Schmollinger JC, Noessner E. Progressive natural killer cell dysfunction associated with alterations in subset proportions and receptor expression in soft-tissue sarcoma patients. Oncoimmunology. 2016;5(7):e1178421. .

  33. Burke S, Lakshmikanth T, Colucci F, Carbone E. New views on natural killer cell-based immunotherapy for melanoma treatment. Trends Immunol. 2010;31(9):339-45. .

  34. Jurisic V, Srdic T, Konjevic G, Markovic O, Colovic M. Clinical stage-depending decrease of NK cell activity in multiple myeloma patients. Med Oncol. 2007;24(3):312-7. .

  35. Kaur K, Topchyan P, Kozlowska AK, Ohanian N, Chiang J, Maung PO, Park SH, Ko MW, Fang C, Nishimura I, Jewett A. Super-charged NK cells inhibit growth and progression of stem-like/poorly differentiated oral tumors in vivo in humanized BLT mice; effect on tumor differentiation and response to chemotherapeutic drugs. Oncoimmunology. 2018;7(5):e1426518. .

  36. Jewett A, Cavalcanti M, Bonavida B. Pivotal role of endogenous TNF-a in the induction of functional in-activation and apoptosis in NK cells. J Immunol. 1997;159(10):4815-22. .

  37. Jewett A, Bonavida B. Target-induced inactivation and cell death by apoptosis in a subset of human NK cells. J Immunol. 1996;156(3):907-15. .

  38. Jewett A, Bonavida B. Target-induced anergy of natural killer cytotoxic function is restricted to the NK-target conjugate subset. Cell Immunol. 1995;160(1):91-7. .

  39. Woroniecka K, Chongsathidkiet P, Rhodin KE, Kemeny HR, Dechant C, Farber SH, Elsamadicy AA, Cui X, Koyama S, Jackson C, Hansen LJ, Johanns TM, Sanchez-Perez L, Chandramohan V, Yu YA, Bigner DD, Giles A, Healy P, Dranoff G, Weinhold KJ, Dunn GP, Fecci PE. T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma. Clin Cancer Res. 2018 Sep 1;24(17):4175-86. .

  40. Bonavida B, Lebow LT, Jewett A. Natural killer cell subsets: maturation, differentiation and regulation. Nat Im mun. 1993;12(4-5):194-208. .

  41. Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, Stassi G. Colon cancer stem cells dictate tumor growth and resist cell death by production of inter-leukin-4. Cell Stem Cell. 2007;1(4):389-402. .

  42. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111-5. .

  43. Toden S, Ravindranathan P, Gu J, Cardenas J, Yuchang M, Goel A. Oligomeric proanthocyanidins (OPCs) target cancer stem-like cells and suppress tumor organoid formation in colorectal cancer. Sci Rep. 2018;8(1):3335. .

  44. Guo Z, Hardin H, Lloyd RV. Cancer stem-like cells and thyroid cancer. Endocr Relat Cancer. 2014 Oct; 21(5):T285-300. .

  45. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci. 2007;104(3):973-8. .

  46. Hu Z, Xu J, Cheng J, McMichael E, Yu L, Carson 3rd WE. Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines, tumor xenografts and patients of breast, lung and ovarian cancer. Oncotarget. 2017;8(1):1481-94. .

  47. Jewett A, Arasteh A, Tseng HC, Behel A, Arasteh H, Yang W, Cacalano NA, Paranjpe A. Strategies to rescue mesenchymal stem cells (MSCs) and dental pulp stem cells (DPSCs) from NK cell mediated cytotoxicity. PLoS One. 2010;5(3):e9874. .

  48. Ichise H, Nagano S, Maeda T, Miyazaki M, Miyazaki Y, Kojima H, Yawata N, Yawata M, Tanaka H, Saji H, Masuda K, Kawamoto H. NK cell alloreactivity against KIR-ligand-mismatched HLA-haploidentical tissue derived from HLA haplotype-homozygous iPSCs. Stem Cell Rep. 2017;9(3):853-67. .

  49. Jewett A, Tseng HC, Arasteh A, Saadat S, Christensen RE, Cacalano NA. Natural killer cells preferentially target cancer stem cells; role of monocytes in protection against NK cell mediated lysis of cancer stem cells. Curr Drug Deliv. 2012;9(1):5-16. .

  50. Ames E, Canter RJ, Grossenbacher SK, Mac S, Chen M, Smith RC, Hagino T, Perez-Cunningham J, Sckisel GD, Urayama S, Monjazeb AM, Fragoso RC, Sayers TJ, Murphy WJ. NK cells preferentially target tumor cells with a cancer stem cell phenotype. J Immunol. 2015; 195(8):4010-9. .

  51. Jewett A, Man YG, Tseng HC. Dual functions of natural killer cells in selection and differentiation of stem cells; role in regulation of inflammation and regeneration of tissues. J Cancer. 2013;4(1):12-24. .

  52. Lee BC, Kim MS, Pae M, Yamamoto Y, Eberle D, Shimada T, Kamei N, Park HS, Sasorith S, Woo JR, You J, Mosher W, Brady HJ, Shoelson SE, Lee J. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metabol. 2016;23(4):685-98. .

  53. Bonamichi B, Lee J. Unusual suspects in the development of obesity-induced inflammation and insulin resistance: NK cells, iNKT cells, and ILCs. Diabet Metabol J. 2017;41(4):229-50. .

  54. Kozlowska AK, Tseng HC, Kaur K, Topchyan P, Inagaki A, Bui VT, Kasahara N, Cacalano N, Jewett A. Resistance to cytotoxicity and sustained release of inter-leukin-6 and interleukin-8 in the presence of decreased interferon-y after differentiation of glioblastoma by human natural killer cells. Cancer Immunol Immunother. 2016;65(9):1085-97. .

  55. Bui VT, Tseng HC, Kozlowska A, Maung PO, Kaur K, Topchyan P, Jewett A. Augmented IFN-y and TNF-a induced by probiotic bacteria in nk cells mediate differentiation of stem-like tumors leading to inhibition of tumor growth and reduction in inflammatory cytokine release; regulation by IL-10. Front Immunol. 2015;6:576. .

  56. Wang B, Wang Q, Wang Z, Jiang J, Yu SC, Ping YF, Yang J, Xu SL, Ye XZ, Xu C, Yang L, Qian C, Wang JM, Cui YH, Zhang X, Bian XW. Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells. Cancer Res. 2014;74(20):5746-57. .

  57. Tseng HC, Bui V, Man YG, Cacalano N, Jewett A. Induction of split anergy conditions natural killer cells to promote differentiation of stem cells through cell-cell contact and secreted factors. Front Immunol. 2014;5:269. .

  58. Tseng HC, Inagaki A, Bui VT, Cacalano N, Kasahara N, Man YG, Jewett A. Differential targeting of stem cells and differentiated glioblastomas by NK cells. J Cancer. 2015;6(9):866-76. .

  59. Jewett A, Tseng HC. Tumor microenvironment may shape the function and phenotype of NK cells through the induction of split anergy and generation of regulatory NK cells. In: Shurin M, Umansky V, Malyguine A, editors. The tumor immunoenvironment. The Netherlands: Springer; 2013. p. 361-84. .

  60. Kaur K, Kozlowska AK, Topchyan P, Ko MW, Ohanian N, Chiang J, Cook J, Maung PO, Park SH, Cacalano N, Fang C, Jewett A. Probiotic-treated super-charged NK cells efficiently clear poorly differentiated pancreatic tumors in Hu-BLT mice. Cancers. 2019;12(1):63. doi: 10.3390/ cancers12010063. .

  61. Jewett A, Man YG, Cacalano N, Kos J, Tseng HC. Natural killer cells as effectors of selection and differentiation of stem cells: role in resolution of inflammation. J Immuno-toxicol. 2014;11(4):297-307. .

  62. Shan Y, He X, Song W, Han D, Niu J, Wang J. Role of IL-6 in the invasiveness and prognosis of glioma. Int J Clin Exp Med. 2015;8(6):9114-20. .

  63. Xie K. Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev. 2001;12(4):375-91. .

  64. Sasaki A, Ishiuchi S, Kanda T, Hasegawa M, Nakazato Y. Analysis of interleukin-6 gene expression in primary human gliomas, glioblastoma xenografts, and glioblastoma cell lines. Brain Tumor Pathol. 2001;18(1):13-21. .

  65. Desbaillets I, Diserens AC, de Tribolet N, Hamou MF, Van Meir EG. Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma. Oncogene. 1999;18(7):1447-56. .

  66. Desbaillets I, Diserens AC, Tribolet N, Hamou MF, Van Meir EG. Upregulation of interleukin 8 by oxygen-deprived cells in glioblastoma suggests a role in leukocyte activation, chemotaxis, and angiogenesis. J Exp Med. 1997;186(8):1201-12. .

  67. Tada M, Suzuki K, Yamakawa Y, Sawamura Y, Sakuma S, Abe H, Van Meir E, De Tribolet N. Human glioblastoma cells produce 77 amino acid interleukin-8 (IL-8(77)). J Neurooncol. 1993;16(1):25-34. .

  68. Van Meir E, Ceska M, Effenberger F, Walz A, Grouzmann E, Desbaillets I, Frei K, Fontana A, De Tribolet N. Interleukin-8 is produced in neoplastic and infectious diseases of the human central nervous system. Cancer Res. 1992;52(16):4297-305. .

  69. Nakazawa T, Nakamura M, Park YS, Motoyama Y, Hironaka Y, Nishimura F, Nakagawa I, Yamada S, Matsuda R, Tamura K, Sugimoto T, Takeshima Y, Marutani A, Tsujimura T, Ouji N, Ouji Y, Yoshikawa M, Nakase H. Cytotoxic human peripheral blood-derived yS T cells kill glioblastoma cell lines: implications for cell-based immunotherapy for patients with glioblastoma. J Neurooncol. 2014;116(1):31-9. .

  70. Finocchiaro G, Pellegatta S. Perspectives for immunotherapy in glioblastoma treatment. Curr Opin Oncol. 2014;26(6):608-14. .

  71. Breznik B, Motaln H, Vittori M, Rotter A, Lah Turnsek T. Mesenchymal stem cells differentially affect the invasion of distinct glioblastoma cell lines. Oncotarget. 2017;8(15):25482-99. .

  72. Lah TT, Novak M, Breznik B. Brain malignancies: glio-blastoma and brain metastases. Semin Cancer Biol. 2019 (in press). .

  73. Haspels HN, Rahman MA, Joseph JV, Gras Navarro A, Chekenya M. Glioblastoma stem-like cells are more susceptible than differentiated cells to natural killer cell lysis mediated through killer immunoglobulin-like receptors-human leukocyte antigen ligand mismatch and activation receptor-ligand interactions. Front Immunol. 2018;9:1345. .

  74. Chanvillard C, Jacolik RF, Infante-Duarte C, Nayak RC. The role of natural killer cells in multiple sclerosis and their therapeutic implications. Front Immunol. 2013;4:63. .

  75. Kaur G, Trowsdale J, Fugger L. Natural killer cells and their receptors in multiple sclerosis. Brain. 2013;136(Pt 9):265-76. .

  76. Poli A, Kmiecik J, Domingues O, Hentges F, Blery M, Chekenya M, Boucraut J, Zimmer J. NK cells in central nervous system disorders. J Immunol. 2013;190(11): 5355-62. .

  77. Lamano JB, Lamano JB, Li YD, DiDomenico JD, Choy W, Veliceasa D, Oyon DE, Fakurnejad S, Ampie L, Kesavabhotla K, Kaur R, Kaur G, Biyashev D, Unruh DJ, Horbinski CM, James CD, Parsa AT, Bloch O. Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth. Clin Cancer Res. 2019;25(12):3643-57. .

  78. Golan I, Rodriguez de la Fuente L, Costoya JA. NK Cell-based glioblastoma immunotherapy. Cancers (Basel). 2018 Dec 18;10(12):E522. .

  79. Zhang C, Burger MC, Jennewein L, Genssler S, Schonfeld K, Zeiner P, Hattingen E, Harter PN, Mittelbronn M, Tonn T, Steinbach JP, Wels WS. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. J Natl Cancer Inst. 2016;108(5). doi: 10.1093/jncl/djv375. .

  80. Poli A, Wang J, Domingues O, Planaguma J, Yan T, Rygh CB, Skaftnesmo KO, Thorsen F, McCormack E, Hentges F, Pedersen PH, Zimmer J, Enger P0, Chekenya M. Targeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survival. Oncotarget. 2013; 4(9):1527-46. .

  81. Tanaka H, Nakao M, Shichijo S, Itoh K. Nonsteroidal anti-inflammatory drugs differentially regulate cytokine production in human lymphocytes: up-regulation of TNF, IFN-y and IL-2, in contrast to down-regulation of IL-6 production. Cytokine. 1995;7(4):372-9. .

  82. Miescher S, Stoeck M, Qiao L, Barras C, Barrelet L, von Fliedner V. Preferential clonogenic deficit of CD8-positive T-lymphocytes infiltrating human solid tumors. CanAer Res. 1988;48(24 Pt 1):6992-8. .

  83. Qin J, Han B, Pang J. The relationship between TIL from human primary hepatic carcinoma and prognosis. Zhonghua Yi Xue Za Zhi. 1997;77(3):167-70. .

  84. Han X, Papadopoulos AJ, Ruparelia V, Devaja O, Raju KS. Tumor lymphocytes in patients with advanced ovarian cancer: changes during in vitro culture and implications for immunotherapy. Gynecol Oncol. 1997;65(3):391-8. .

  85. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006;9(5):391-403. .

  86. Castriconi R, Daga A, Dondero A, Zona G, Poliani PL, Melotti A, Griffero F, Marubbi D, Spaziante R, Bellora F, Moretta L, Moretta A, Corte G, Bottino C. NK cells recognize and kill human glioblastoma cells with stem cell-like properties. J Immunol. 2009;182(6):3530-9. .

  87. Barak H, Huh SH, Chen S, Jeanpierre C, Martinovic J, Parisot M, Bole-Feysot C, Nitschke P, Salomon R, Antignac C, Ornitz DM, Kopan R. FGF9 and FGF20 Maintain the stemness of nephron progenitors in mice and man. Dev Cell. 2012;22(6):1191-207. .

  88. Coutu DL, Galipeau J. Roles of FGF signaling in stem cell self-renewal, senescence and aging. Aging. 2011;3(10):920-33. .

  89. Tseng HC, Arasteh A, Kaur K, Kozlowska A, Topchyan P, Jewett A. Differential cytotoxicity but augmented IFN-y secretion by NK cells after interaction with monocytes from humans, and those from wild type and myeloid-specific COX-2 knockout mice. Front Immunol. 2015;6:259. .

  90. Tato CM, Mason N, Artis D, Shapira S, Caamano JC, Bream JH, Liou HC, Hunter CA. Opposing roles of NF-KB family members in the regulation of NK cell proliferation and production of IFN-y. Int Immunol. 2006;18(4):505-13. .

  91. Barta P, Van Pelt C, Men T, Dickey BF, Lotan R, Moghaddam SJ. Enhancement of lung tumorigenesis in a Gprc5a knockout mouse by chronic extrinsic airway inflammation. Mol Cancer. 2012;11:4. .

  92. Deng J, Fujimoto J, Ye XF, Men TY, Van Pelt CS, Chen YL, Lin XF, Kadara H, Tao Q, Lotan D, Lotan R. Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-KB activation in airway epithelium and promotes lung inflammation and tumorigenesis. Cancer Prev Res (Phila). 2010;3(4):424-37. .

  93. Bedel R, Thiery-Vuillemin A, Grandclement C, Balland J, Remy-Martin JP, Kantelip B, Pallandre JR, Pivot X, Ferrand C, Tiberghien P, Borg C. Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells. Cancer Res. 2011;71(5):1615-26. .

  94. Ihara S, Kida H, Arase H, Tripathi LP, Chen YA, Kimura T, Yoshida M, Kashiwa Y, Hirata H, Fukamizu R, Inoue R, Hasegawa K, Goya S, Takahashi R, Minami T, Tsujino K, Suzuki M, Kohmo S, Inoue K, Nagatomo I, Takeda Y, Kijima T, Mizuguchi K, Tachibana I, Kumanogoh A. Inhibitory roles of signal transducer and activator of transcription 3 in antitumor immunity during carcinogen-induced lung tumorigenesis. Cancer Res. 2012;72(12):2990-9. .

  95. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mule J, Kerr WG, Jove R, Pardoll D, Yu H. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005;11(12):1314-21. .

  96. van Helden YG, Heil SG, van Schooten FJ, Kramer E, Hessel S, Amengual J, Ribot J, Teerds K, Wyss A, Lietz G, Bonet ML, von Lintig J, Godschalk RW, Keijer J. Knockout of the Bcmo1 gene results in an inflammatory response in female lung, which is suppressed by dietary P-carotene. Cell Mol Life Sci. 2010;67(12):2039-56. .

  97. Kohga K, Tatsumi T, Takehara T, Tsunematsu H, Shimizu S, Yamamoto M, Sasakawa A, Miyagi T, Hayashi N. Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma. J Hepatol. 2010;52(6):87-29. .

  98. Schmohl JU, Gleason MK, Dougherty PR, Miller JS, Vallera DA. Heterodimeric bispecific single chain variable fragments (scFv) killer engagers (BiKEs) enhance NK-cell activity against CD133+ colorectal cancer cells. Target Oncol. 2016;11(3):353-61 .

  99. Gironella M, Folch-Puy E, LeGoffic A, Garcia S, Christa L, Smith A, Tebar L, Hunt SP, Bayne R, Smith AJ, Dagorn JC, Closa D, Iovanna JL. Experimental acute pancreatitis in PAP/HIP knock-out mice. Gut. 2007;56(8):1091-7. .

  100. Lv Y, Yang X, Huo Y, Tian H, Li S, Yin Y, Hao Z. Adenovirus-mediated hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein suppresses dextran sulfate sodium-induced acute ulcerative colitis in rats. Inflamm Bowel Dis. 2012;18(10):1950-60. .

  101. Beraza N, Malato Y, Sander LE, Al-Masaoudi M, Freimuth J, Riethmacher D, Gores GJ, Roskams T, Liedtke C, Trautwein C. Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. J Exp Med. 2009;206(8):1727-37. .

  102. Orange JS, Brodeur SR, Jain A, Bonilla FA, Schneider LC, Kretschmer R, Nurko S, Rasmussen WL, Kohler JR, Gellis SE, Ferguson BM, Strominger JL, Zonana J, Ramesh N, Ballas ZK, Geha RS. Deficient natural killer cell cytotoxicity in patients with IKK-y/NEMO mutations. J Clin Invest. 2002;109(11):1501-9. .

  103. Pachlopnik Schmid JM, Junge SA, Hossle JP, Schneider EM, Roosnek E, Seger RA, Gungor T. Transient hemophagocytosis with deficient cellular cytotoxicity, monoclonal immunoglobulin M gammopathy, increased T-cell numbers, and hypomorphic NEMO mutation. Pediatrics. 2006;117(5):e1049-56. .

  104. Lee YS, Yeo IJ, Kim KC, Han SB, Hong JT. Inhibition of lung tumor development in ApoE knockout mice via enhancement of TREM-1 dependent NK cell cytotoxicity. Front Immunol. 2019;10:1379. .

  105. Guo L, LaDu MJ, Van Eldik LJ. A dual role for apolipoprotein E in neuroinflammation: anti- and pro-inflammatory activity. J Mol Neurosci. 2004;23(3):205-12. .

  106. Romero-Reyes M, Head C, Cacalano NA, Jewett A. Potent induction of TNF-a during interaction of immune effectors with oral tumors as a potential mechanism for the loss of NK cell viability and function. Apoptosis. 2007;12(11):2063-75. .

  107. Xu L, Chen X, Shen M, Yang DR, Fang L, Weng G, Tsai Y, Keng PC, Chen Y, Lee SO. Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels. Mol Oncol. 2018;12(3):269-86. .

  108. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim BiophysActa. 2011;1813(5):878-88. .

  109. Cifaldi L, Prencipe G, Caiello I, Bracaglia C, Locatelli F, De Benedetti F, Strippoli R. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol. 2015;67(11):3037-46. .

  110. Wu J, Gao FX, Wang C, Qin M, Han F, Xu T, Hu Z, Long Y, He XM, Deng X, Ren DL, Dai TY. IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma. J Exp Clin Cancer Res. 2019;38(1):321. .

  111. Lanier LL. DAP10- and DAP12-associated receptors in innate immunity. Immunol Rev. 2009;227(1):150-60. .

  112. Alex P, Ye M, Zachos NC, Sipes J, Nguyen T, Suhodrev M, Gonzales L, Arora Z, Zhang T, Centola M, Guggino SE, Li X. Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis. J Immunol. 2010;184(7):3988-96. .

  113. Parameswaran R, Ramakrishnan P, Moreton SA, Xia Z, Hou Y, Lee DA, Gupta K, deLima M, Beck RC, Wald DN. Repression of GSK3 restores NK cell cytotoxicity in AML patients. Nat Commun. 2016;7:11154. .

  114. Cichocki F, Valamehr B, Bjordahl R, Zhang B, Rezner B, Rogers P, Gaidarova S, Moreno S, Tuininga K, Dougherty P, McCullar V, Howard P, Sarhan D, Taras E, Schlums H, Abbot S, Shoemaker D, Bryceson YT, Blazar BR, Wolchko S, Cooley S, Miller JS. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Cancer Res. 2017;77(20):5664-75. .

  115. Cortes-Vieyra R, Bravo-Patino A, Valdez-Alarcon JJ, Juarez MC, Finlay BB, Baizabal-Aguirre VM. Role of glycogen synthase kinase-3 p in the inflammatory response caused by bacterial pathogens. J Inflamm (Lond). 2012;9(1):23. .

  116. Aoukaty A, Tan R. Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease. J Immunol. 2005;174(8):4551-8. .

  117. Thompson WL, Karpus WJ, Van Eldik LJ. MCP-1-deficient mice show reduced neuroinflammatory responses and increased peripheral inflammatory responses to peripheral endotoxin insult. J Neuroinflamm. 2008;5:35. .

  118. Xu X, Wang Q, Deng B, Wang H, Dong Z, Qu X, Kong B. Monocyte chemoattractant protein-1 secreted by decidual stromal cells inhibits NK cells cytotoxicity by up-regulating expression of SOCS3. PLoS One. 2012;7(7):e41869. .

  119. Pham DH, Kim JS, Kim SK, Shin DJ, Uong NT, Hyun H, Yoon MS, Kang SJ, Ryu YJ, Cho JS, Yoon JH, Lee JS, Cho D, Lee SH, Park MH. Effects of ADAM10 and ADAM17 inhibitors on natural killer cell expansion and antibody-dependent cellular cytotoxicity against breast cancer cells in vitro. Anticancer Res. 2017;37(10):5507-13. .

  120. Tsukerman P, Eisenstein EM, Chavkin M, Schmiedel D, Wong E, Werner M, Yaacov B, Averbuch D, Molho-Pessach V, Stepensky P, Kaynan N, Bar-On Y, Seidel E, Yamin R, Sagi I, Elpeleg O, Mandelboim O. Cytokine secretion and NK cell activity in human ADAM17 deficiency. Oncotarget. 2015;6(42):44151-60. .

  121. Bognar P, Nemeth I, Mayer B, Haluszka D, Wikonkal N, Ostorhazi E, John S, Paulsson M, Smyth N, Pasztoi M, Buzas EI, Szipocs R, Kolonics A, Temesvari E, Karpati S. Reduced inflammatory threshold indicates skin barrier defect in transglutaminase 3 knockout mice. J Invest Dermatol. 2014;134(1):105-11. .

  122. Furutani E, Su S, Smith A, Berg M, Childs R. siRNA in-activation of the inhibitory receptor NKG2A augments the anti-tumor effects of adoptively transferred NK cells in tumor-bearing hosts. Blood. 2010;116(21):1015. .

  123. Kamiya T, Seow SV, Wong D, Robinson M, Campana D. Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells. J Clin Invest. 2019;129(5):2094-106. .

  124. Beglopoulos V, Sun X, Saura CA, Lemere CA, Kim RD, Shen J. Reduced P-amyloid production and increased in-flammatory responses in presenilin conditional knock-out mice. J Biol Chem. 2004;279(45):46907-14. .

  125. Suarez-Fueyo A, Bradley SJ, Katsuyama T, Solomon S, Katsuyama E, Kyttaris VC, Moulton VR, Tsokos GC. Downregulation of CD3Z in NK cells from systemic lupus erythematosus patients confers a proinflammatory phenotype. J Immunol. 2018;200(9):3077-86. .

  126. Roviezzo F, Getting SJ, Paul-Clark MJ, Yona S, Gavins FN, Perretti M, Hannon R, Croxtall JD, Buckingham JC, Flower RJ. The annexin-1 knockout mouse: What it tells us about the inflammatory response. J Physiol Pharmacol. 2002;53(4 Pt 1):541-53. .

  127. Bergstrom I, Lundberg AK, Jonsson S, Sarndahl E, Ernerudh J, Jonasson L. Annexin A1 in blood mononuclear cells from patients with coronary artery disease: its association with inflammatory status and glucocorticoid sensitivity. PLoS One. 2017;12(3):e0174177. .

  128. Long Y, Gao Z, Hu X, Xiang F, Wu Z, Zhang J, Han X, Yin L, Qin J, Lan L, Yin F, Wang Y. Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma. Cancer Med. 2018;7(9):4690-700. .

  129. Guedes RP, Csizmadia E, Moll HP, Ma A, Ferran C, da Silva CG. A20 deficiency causes spontaneous neuroin-flammation in mice. J Neuroinflamm. 2014;11:122. .

  130. Daniel S, Arvelo MB, Patel VI, Longo CR, Shrikhande G, Shukri T, Mahiou J, Sun DW, Mottley C, Grey ST, Ferran C. A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation. Blood. 2004;104(8):2376-84. .

  131. Verdeil G, Schmitt-Verhulst AM. Unleashing antitumor T-cell activation without ensuing autoimmunity: the case for A20-deletion in adoptive CD8+ T-cell therapy. Onco-immunology. 2014;3(10):e958951. .

  132. Kim HS, Das A, Gross CC, Bryceson YT, Long EO. Synergistic signals for natural cytotoxicity are required to overcome inhibition by c-Cbl ubiquitin ligase. Immunity. 2010;32(2):175-86. .

  133. Dong L, Li YZ, An HT, Wang YL, Chen SH, Qian YJ, Wang K, Zhen JL, Fan Z, Gong XL, Zheng Y, Wang XM. The E3 ubiquitin ligase c-Cbl inhibits microglia-mediated CNS inflammation by regulating PI3K/Akt/NF-KB pathway. CNS Neurosci Ther. 2016;22(8):661-9. .

  134. Baker GJ, Chockley P, Yadav VN, Doherty R, Ritt M, Sivaramakrishnan S, Castro MG, Lowenstein PR. Natural killer cells eradicate galectin-1-deficient glioma in the absence of adaptive immunity. Cancer Res. 2014;74(18):5079-90. .

  135. Mendez-Huergo SP, Hockl PF, Stupirski JC, Maller SM, Morosi LG, Pinto NA, Beron AM, Musuruana JL, Nasswetter GG, Cavallasca JA, Rabinovich GA. Clinical relevance of galectin-1 and galectin-3 in rheumatoid arthritis patients: differential regulation and correlation with disease activity. Front Immunol. 2018;93057. .

  136. Bugide S, Green MR, Wajapeyee N. Inhibition of enhancer of zeste homolog 2 (EZH2) induces natural killer cell-mediated eradication of hepatocellular carcinoma cells. Proc Natl Acad Sci. 2018;115(15):E3509-e18. .

  137. Ramakrishnan S, Granger V, Rak M, Hu Q, Attwood K, Aquila L, Krishnan N, Osiecki R, Azabdaftari G, Guru K, Chatta G, Gueron G, McNally L, Ohm J, Wang J, Woloszynska A. Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer. Cell Death Differ. 2019;26(10):2100-14. .

  138. Yin J, Leavenworth JW, Li Y, Luo Q, Xie H, Liu X, Huang S, Yan H, Fu Z, Zhang LY, Zhang L, Hao J, Wu X, Deng X, Roberts CW, Orkin SH, Cantor H, Wang X. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc Natl Acad Sci. 2015;112(52):15988-93. .

  139. Radosavljevic G, Jovanovic I, Majstorovic I, Mitrovic M, Lisnic VJ, Arsenijevic N, Jonjic S, Lukic ML. Deletion of galectin-3 in the host attenuates metastasis of murine melanoma by modulating tumor adhesion and NK cell activity. Clin Exp Metastasis. 2011;28(5):451-62. .

  140. Wang W, Guo H, Geng J, Zheng X, Wei H, Sun R, Tian Z. Tumor-released galectin-3, a soluble inhibitory ligand of human NKp30, plays an important role in tumor escape from NK cell attack. J Biol Chem. 2014;289(48):33311-9. .

  141. Purdy AK, Campbell KS. SHP-2 Expression negatively regulates NK cell function. J Immunol. 2009;183(11):7234-43. .

  142. Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur NK, Yan Z, Spiegelman BM. Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1a muscle-specific knock-out animals. J Biol Chem. 2007;282(41):30014-21. .

  143. Miranda D, Jara C, Ibanez J, Ahumada V, Acuna-Castillo C, Martin A, Cordova A, Montoya M. PGC-1a-dependent mitochondrial adaptation is necessary to sustain IL-2-induced activities in human NK cells. Mediators Inflamm. 2016;2016:9605253. .

  144. Lametschwandtner G, Sachet M, Haslinger I, Muhleisen H, Loibner H. Cbl-b silenced human NK cells respond stronger to cytokine stimulation. J Immunother Cancer. 2015;3(Suppl 2):P230. .

  145. Lokody I. Loss of Cbl-b unleashes anti-metastatic natural killer cells. Nat Rev Cancer. 2014;14(4):218. .

  146. Bieghs V, Van Gorp PJ, Wouters K, Hendrikx T, Gijbels MJ, van Bilsen M, Bakker J, Binder CJ, Lutjohann D, Staels B, Hofker MH, Shiri-Sverdlov R. LDL receptor knock-out mice are a physiological model particularly vulnerable to study the onset of inflammation in non-alcoholic fatty liver disease. PLoS One. 2012;7(1):e30668 .

  147. De Sanctis JB, Blanca I, Radzioch D, Bianco NE. Expression and function of low-density lipoprotein receptors in CD3-CD16+CD56+ cells: effect of interleukin 2. Cell Immunol. 1996;167(1):18-29. .

  148. Liu B, Qu L, Yan S. Cyclooxygenase-2 promotes tumor growth and suppresses tumor immunity. Cancer Cell Int. 2015;15:106. .

  149. Zhu X, Lee JY, Timmins JM, Brown JM, Boudyguina E, Mulya A, Gebre AK, Willingham MC, Hiltbold EM, Mishra N, Maeda N, Parks JS. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J Biol Chem. 2008;283(34):22930-41. .

  150. Bochem AE, van der Valk FM, Tolani S, Stroes ES, Westerterp M, Tall AR. Increased systemic and plaque inflammation in abca1 mutation carriers with attenuation by statins. Arterioscler Thromb Vasc Biol. 2015;35(7):1663-9. .

  151. Yin K, Liao DF, Tang CK. ATP-binding membrane cassette transporter A1 (ABCA1): a possible link between inflammation and reverse cholesterol transport. Mol Med. 2010;16(9-10):438-49. .

  152. Cacalano NA, Le D, Paranjpe A, Wang MY, Fernandez A, Evazyan T, Park NH, Jewett A. Regulation of IG-FBP6 gene and protein is mediated by the inverse expression and function of c-jun N-terminal kinase (JNK) and NFKB in a model of oral tumor cells. Apoptosis. 2008;13(12):1439-49. .

  153. Fu XY. STAT3 in immune responses and inflammatory bowel diseases. Cell Res. 2006;16(2):214-9. .

  154. Jewett A, Cacalano NA, Teruel A, Romero M, Rashedi M, Wang M, Nakamura H. Inhibition of nuclear factor KB (NFKB) activity in oral tumor cells prevents depletion of NK cells and increases their functional activation. Cancer Immunol Immunother. 2006;55(9):1052-63. .

  155. Jewett A, Wang MY, Teruel A, Poupak Z, Bostanian Z, Park NH. Cytokine dependent inverse regulation of CD54 (iCAM1) and major histocompatibility complex class I antigens by nuclear factor KB in HEp2 tumor cell line: effect on the function of natural killer cells. Hum Immunol. 2003;64(5):505-20. .

  156. Wu J, Cherwinski H, Spies T, Phillips JH, Lanier LL. DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells. J Exp Med. 2000;192(7):1059-68. .

  157. Perisic Nanut M, Sabotic J, Svajger U, Jewett A, Kos J. Cystatin F affects natural killer cell cytotoxicity. Front Immunol. 2017;8:1459. .

  158. Konjar S, Sutton VR, Hoves S, Repnik U, Yagita H, Re-inheckel T, Peters C, Turk V, Turk B, Trapani JA, Kopitar-Jerala N. Human and mouse perforin are processed in part through cleavage by the lysosomal cysteine proteinase cathepsin L. Immunology. 2010;131(2):257-67. .

  159. D'Angelo ME, Bird PI, Peters C, Reinheckel T, Trapani JA, Sutton VR. Cathepsin H is an additional convertase of progranzyme B. J Biol Chem. 2010;285(27):20514-9. .

  160. Sutton VR, Waterhouse NJ, Browne KA, Sedelies K, Ciccone A, Anthony D, Koskinen A, Mullbacher A, Trapani JA. Residual active granzyme B in cathepsin C-null lymphocytes is sufficient for perforindependent target cell apoptosis. J Cell Biol. 2007;176(4):425-33. .

  161. Langerholc T, Zavasnik-Bergant V, Turk B, Turk V, Abrahamson M, Kos J. Inhibitory properties of cystatin F and its localization in U937 promonocyte cells. FEBS J. 2005;272(6):1535-45. .

  162. Maher K, Konjar S, Watts C, Turk B, Kopitar-Jerala N. Cystatin F regulates proteinase activity in IL-2-activated natural killer cells. Protein Pept Lett. 2014;21(9):957-65. .

  163. Colbert JD, Plechanovova A, Watts C. Glycosylation directs targeting and activation of cystatin F from intracellular and extracellular sources. Traffic. 2009;10(4):425-37. .

  164. Colbert JD, Matthews SP, Kos J, Watts C. Internalization of exogenous cystatin F supresses cysteine proteases and induces the accumulation of singlechain cathepsin L by multiple mechanisms. J Biol Chem. 2011;286(49):42082-90. .

  165. Prunk M, Nanut MP, Sabotic J, Svajger U, Kos J. Increased cystatin F levels correlate with decreased cytotoxicity of cytotoxic T cells. Radiol Oncol. 2019;53(1):57-68. .

  166. Pham CT, Ley TJ. Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc Natl Acad Sci. 1999;96(15):8627-32. .

  167. Chan CB, Abe M, Hashimoto N, Hao C, Williams IR, Liu X, Nakao S, Yamamoto A, Zheng C, Henter JI, Meeths M, Nordenskjold M, Li SY, Hara-Nishimura I, Asano M, Ye K. Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome. Proc Natl Acad Sci. 2009;106(2):468-73. .

  168. Magister S, Kos J. Cystatins in immune system. J Cancer. 2013;4(1):45-56. .

  169. Hamilton G, Colbert JD, Schuettelkopf AW, Watts C. Cystatin F is a cathepsin C-directed protease inhibitor regulated by proteolysis. EMBO J. 2008;27(3):499-508. .

  170. Gogali F, Paterakis G, Rassidakis GZ, Liakou CI, Liapi C. CD3-CD16-CD56bright immunoregulatory NK cells are increased in the tumor microenvironment and inversely correlate with advanced stages in patients with papillary thyroid cancer. Thyroid. 2013;23(12):1561-8. .

  171. Lopez-Cobo S, Pieper N, Campos-Silva C, Garcia-Cuesta EM, Reyburn HT, Paschen A, Vales-Gomez M. Impaired NK cell recognition of vemurafenib-treated melanoma cells is overcome by simultaneous application of histone deacetylase inhibitors. Oncoimmunology. 2018;7(2):e1392426. .

  172. Ciszak L, Kosmaczewska A, Werynska B, Szteblich A, Jankowska R, Frydecka I. Impaired Z chain expression and IFN-y production in peripheral blood T and NK cells of patients with advanced lung cancer. Oncol Rep. 2009;21(1):173-84. .

  173. Vitale M, Cantoni C, Pietra G, Mingari MC, Moretta L. Effect of tumor cells and tumor microenvironment on NK cell function. Eur J Immunol. 2014;44(6):1582-92. .

  174. Viel S, Marcais A, Guimaraes FS, Loftus R, Rabilloud J, Grau M, Degouve S, Djebali S, Sanlaville A, Charrier E, Bienvenu J, Marie JC, Caux C, Marvel J, Town L, Huntington ND, Bartholin L, Finlay D, Smyth MJ, Walzer T. TGF-P inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal. 2016;9(415):ra19. .

  175. Castriconi R, Dondero A, Bellora F, Moretta L, Castellano A, Locatelli F, Corrias MV, Moretta A, Bottino C. Neuroblastoma-derived TGF-P1 modulates the chemokine receptor repertoire of human resting NK cells. J Immunol. 2013;190(10):5321-8. .

  176. Krneta T, Gillgrass A, Chew M, Ashkar AA. The breast tumor microenvironment alters the phenotype and function of natural killer cells. Cell Mol Immunol. 2016;13(5):628-39. .

  177. Pasero C, Gravis G, Guerin M, Granjeaud S, Thomassin-Piana J, Rocchi P, Paciencia-Gros M, Poizat F, Bentobji M, Azario-Cheillan F, Walz J, Salem N, Brunelle S, Moretta A, Olive D. Inherent and tumor-driven immune tolerance in the prostate microenvironment impairs natural killer cell antitumor activity. Cancer Res. 2016;76(8):2153-65. .

  178. Chiu J, Ernst DM, Keating A. Acquired natural killer cell dysfunction in the tumor microenvironment of classic Hodgkin lymphoma. Front Immunol. 2018;9:267. .

  179. Galland S, Vuille J, Martin P, Letovanec I, Caignard A, Fregni G, Stamenkovic I. Tumor-derived mesenchymal stem cells use distinct mechanisms to block the activity of natural killer cell subsets. Cell Rep. 2017;20(12):2891-905. .

  180. Costa D, Vene R, Benelli R, Romairone E, Scabini S, Catellani S, Rebesco B, Mastracci L, Grillo F, Minghelli S, Loiacono F, Zocchi MR, Poggi A. Targeting the epidermal growth factor receptor can counteract the inhibition of natural killer cell function exerted by colorectal tumor-associated fibroblasts. Front Immunol. 2018;9:1150. .

  181. Murray S, Lundqvist A. Targeting the tumor microenvironment to improve natural killer cell-based immunotherapies: on being in the right place at the right time, with resilience. Hum Vaccin Immunother. 2016;12(3):607-11. .

  182. Mao Y, Sarhan D, Steven A, Seliger B, Kiessling R, Lundqvist A. Inhibition of tumor-derived prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clin Cancer Res. 2014;20(15):4096-106. .

  183. O'Brien KL, Finlay DK. Immunometabolism and natural killer cell responses. Nat Rev Immunol. 2019;19(5):282-90. .

  184. Young A, Ngiow SF, Gao Y, Patch AM, Barkauskas DS, Messaoudene M, Lin G, Coudert JD, Stannard KA, Zitvogel L, Degli-Esposti MA, Vivier E, Waddell N, Linden J, Huntington ND, Souza-Fonseca-Guimaraes F, Smyth MJ. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res. 2018;78(4):1003-16. .

  185. Michelet X, Dyck L, Hogan A, Loftus RM, Duquette D, Wei K, Beyaz S, Tavakkoli A, Foley C, Donnelly R, O'Farrelly C, Raverdeau M, Vernon A, Pettee W, O'Shea D, Nikolajczyk BS, Mills KHG, Brenner MB, Finlay D, Lynch L. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat Immunol. 2018;19(12):1330-40. .

  186. Tseng H-C, Kanayama K, Kaur K, Park S-H, Park S, Kozlowska A, Sun S, McKenna CE, Nishimura I, Jewett A. Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: Role in osteoclast-mediated NK cell activation. Oncotarget. 2015;6(24):20002-25. .

  187. Pallmer K, Oxenius A. Recognition and regulation of T cells by NK cells. Front Immunol. 2016;7:251. .

  188. Cook KD, Waggoner SN, Whitmire JK. NK cells and their ability to modulate T cells during virus infections. Crit Rev Immunol. 2014;34(5):359-88. .

  189. Hinrichs CS. A killer sidekick for antitumor T cells. Sci Transl Med. 2019;11(479):eaaw5325. .

  190. Kozlowska AK, Kaur K, Topchyan P, Jewett A. Novel strategies to target cancer stem cells by NK cells; studies in humanized mice. Front Biosci (Landmark Ed). 2017;22:370-84. .

  191. Eser S, Schnieke A, Schneider G, Saur D. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer. 2014;111(5):817-22. .

  192. Kim HW, Lee JC, Paik KH, Kang J, Kim J, Hwang JH. Serum interleukin-6 is associated with pancreatic ductal adenocarcinoma progression pattern. Medicine. 2017; 96(5):e5926. .

  193. Long KB, Tooker G, Tooker E, Luque SL, Lee JW, Pan X, Beatty GL. IL6 receptor blockade enhances chemotherapy efficacy in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2017;16(9):1898-908. .

  194. Nagathihalli NS, Castellanos JA, VanSaun MN, Dai X, Ambrose M, Guo Q, Xiong Y, Merchant NB. Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells. Oncotarget. 2016;7(40):65982-92. .

  195. Goumas FA, Holmer R, Egberts JH, Gontarewicz A, Heneweer C, Geisen U, Hauser C, Mende MM, Legler K, Rocken C, Becker T, Waetzig GH, Rose-John S, Kalthoff H. Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrences in orthotopic xenograft models of pancreatic cancer. Int J Cancer. 2015;137(5):1035-46. .

  196. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, Yoshimura A, Reindl W, Sipos B, Akira S, Schmid RM, Algul H. Stat3/Socs3 activation by IL-6 trans-signaling promotes progression of pancreatic in-traepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011;19(4):456-69. .

  197. Xu Y, Sun J, Sheard MA, Tran HC, Wan Z, Liu WY, Asgharzadeh S, Sposto R, Wu HW, Seeger RC. Lena-lidomide overcomes suppression of human natural killer cell anti-tumor functions by neuroblastoma microenvironment-associated IL-6 and TGFpi. Cancer Immunol Immunother. 2013;62(10):1637-48. .

  198. Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T, Eldridge P, Leung WH, Campana D. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 2009;69(9):4010-7. .

  199. LeivasA, Perez-Martinez A, Blanchard MJ, Martin-Clavero E, Fernandez L, Lahuerta JJ, Martinez-Lopez J. Novel treatment strategy with autologous activated and expanded natural killer cells plus anti-myeloma drugs for multiple myeloma. Oncoimmunology. 2016;5(12):e1250051. .

  200. Cekic C, Day YJ, Sag D, Linden J. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res. 2014;74(24):7250-9. .

  201. Anahid J, Janko K, Kawaljit K, Safaei T, Sutanto C, Chen W, Womg P, Namagerdi AK, Fang C, Fomg Y, Ko MW. Natural killer cells: diverse functions in tumor immunity and defects in pre-neoplastic and neoplastic stages of tumorigenesis. Mol Ther Oncolytics. 2019 Nov 29;16:41-52. doi: 10.1016/j.omto.2019.11.002. .

  202. Carlens S, Gilljam M, Chambers BJ, Aschan J, Guven H, Ljunggren HG, Christensson B, Dilber MS. A new method for in vitro expansion of cytotoxic human CD3-CD56+ natural killer cells. Hum Immunol. 2001;62(10):1092-8. .

  203. Spanholtz J, Tordoir M, Eissens D, Preijers F, van der Meer A, Joosten I, Schaap N, De Witte TM, Doistra H. High log-scale expansion of functional human natural killer cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. PLoS One. 2010;5(2):e9221. .

  204. Shah AN, Summy JM, Zhang J, Park SI, Parikh NU, Gallick GE. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol. 2007;14(12):3629-37. .

  205. Muinao T, Deka Boruah HP, Pal M. Diagnostic and prognostic biomarkers in ovarian cancer and the potential roles of cancer stem cells-An updated review. Exper Cell Res. 2018;362(1):1-10. .

  206. Nguyen PH, Giraud J, Chambonnier L, Dubus P, Wittkop L, Belleannee G, Collet D, Soubeyran I, Evrard S, Rousseau B, Senant-Dugot N, Megraud F, Mazurier F, Varon C. Characterization of biomarkers of tumorigenic and chemoresistant cancer stem cells in human gastric carcinoma. Clin Cancer Res. 2017;23(6):1586-97. .

  207. Thompson TW, Kim AB, Li PJ, Wang J, Jackson BT, Huang KTH, Zhang L, Raulet DH. Endothelial cells express NKG2D ligands and desensitize antitumor NK responses. Elife. 2017;6:e30881. .

  208. Pazina T, Shemesh A, Brusilovsky M, Porgador A, Campbell KS. Regulation of the functions of natural cytotoxicity receptors by interactions with diverse ligands and alterations in splice variant expression. Front Immunol. 2017;8:369. .

  209. Ochoa MC, Minute L, Lopez A, Perez-Ruiz E, Gomar C, Vasquez M, Noges S, Etxeberria I, Rodriguez I, Garasa S, Mayer JA, Wirtz P, Melero I, Berraondo P. Enhancement of antibody-dependent cellular cytotoxicity of cetuximab by a chimeric protein encompassing interleukin-15. Onco-immunology. 2018;7(2):e1393597. .

  210. Alderson KL, Sondel PM. Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. J Biomed Biotechnol. 2011;2011:379123. .

  211. Chaurasiya S, Chen NG, Fong Y. Oncolytic viruses and immunity. Curr Opin Immunol. 2018;51:83-90. .

  212. Zamarin D, Wolchok JD. Potentiation of immunomodulatory antibody therapy with oncolytic viruses for treatment of cancer. Mol Ther Oncol. 2014;1:14004. .

  213. Zamarin D, Ricca JM, Sadekova S, Oseledchyk A, Yu Y, Blumenschein WM, Wong J, Gigoux M, Merghoub T, Wolchok JD. PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J Clin Investig. 2018;128(4):1413-28. .

  214. Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P, Merghoub T, Wolchok JD, Allison JP. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med. 2014;6(226):226ra32. .

  215. Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ, Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Chen L, Gorski KS, Anderson AA, Diede SJ, Lassman ME, Gansert J, Hodi FS, Long G. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170(6):1109-19. e10. .

  216. Jarahian M, Watzl C, Fournier P, Arnold A, Djandji D, Zahedi S, Cerwenka A, Paschen A, Schirrmacher V, Momburg F. Activation of natural killer cells by Newcastle disease virus hemagglutinin-neuraminidase. J Virol. 2009;83(16):8108-21. .

  217. Ogbomo H, Zemp FJ, Lun X, Zhang J, Stack D, Rahman MM, McFadden G, Mody CH, Forsyth PA. Myxoma virus infection promotes NK lysis of malignant gliomas in vitro and in vivo. PLoS One. 2013;8(6):e66825. .

  218. Bhat R, Dempe S, Dinsart C, Rommelaere J. Enhancement of NK cell antitumor responses using an oncolytic parvovirus. Int J Cancer. 2011;128(4):908-19. .

  219. Diaz RM, Galivo F, Kottke T, Wongthida P, Qiao J, Thompson J, Valdes M, Barber G, Vile RG. Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. Cancer Res. 2007;67(6):2840-8. .

  220. Tai LH, de Souza CT, Belanger S, Ly L, Alkayyal AA, Zhang J, Rintoul JL, Ananth AA, Lam T, Breitbach CJ, Falls TJ, Kirn DH, Bell JC, Makrigiannis AP, Auer RA. Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells. Cancer Res. 2013;73(1):97-107. .

  221. Ady JW, Heffner J, Klein E, Fong Y. Oncolytic viral therapy for pancreatic cancer: current research and future directions. Oncol Virother. 2014;3:35-46. .

  222. Rahal A, Musher B. Oncolytic viral therapy for pancreatic cancer. J Surg Oncol. 2017;116(1):94-103. .

  223. Benson Jr DM, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK, Greenfield CN, Porcu P, Devine SM, Rotem-Yehudar R, Lozanski G, Byrd JC, Caligiuri MA. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood. 2010;116(13):2286-94. .

  224. Hsu J, Hodgins JJ, Marathe M, Nicolai CJ, Bourgeois-Daigneault MC, Trevino TN, Azimi CS, Scheer AK, Randolph HE, Thompson TW, Zhang L, Iannello A, Mathur N, Jardine KE, Kirn GA, Bell JC, McBurney MW, Raulet DH, Ardolino M. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Investigat. 2018;128(10):4654-68. .

  225. Concha-Benavente F, Kansy B, Moskovitz J, Moy J, Chandran U, Ferris RL. PD-L1 mediates dysfunction in activated PD-1+ NK cells in head and neck cancer patients. Cancer Immunol Res. 2018;6(12):1548-60. .

  226. He Y, Peng H, Sun R, Wei H, Ljunggren HG, Yokoyama WM, Tian Z. Contribution of inhibitory receptor TIGIT to NK cell education. J Autoimmun. 2017;81:1-12. .

  227. Xu F, Sunderland A, Zhou Y, Schulick RD, Edil BH, Zhu Y. Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions. Cancer Immunol Immunother. 2017;66(10):1367-75. .


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