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Critical Reviews™ in Oncogenesis

Published 4 issues per year

ISSN Print: 0893-9675

ISSN Online: 2162-6448

SJR: 0.395 SNIP: 0.322 CiteScore™:: 2.5 H-Index: 54

Indexed in

Immune Responses to BRAF-Targeted Therapy in Melanoma: Is Targeted Therapy Immunotherapy?

Volume 21, Issue 1-2, 2016, pp. 83-91
DOI: 10.1615/CritRevOncog.2016017150
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ABSTRACT

Therapies targeting the mitogen-activated protein kinase signaling pathway can induce profound tumor regression in patients with advanced BRAF-mutated melanoma. Most patients develop resistance after several months of treatment, which is typically followed by rapid disease progression and death. BRAF- and mitogen-activated protein kinase kinase (MEK)-targeted therapies were initially thought to exert their therapeutic effects through direct inhibition of signaling within the tumor cell, resulting in cell death. Recent evidence suggests that BRAF-targeted therapy also augments the host immune response to melanoma. This is characterized by enhanced expression of melanoma differentiation antigens, reduced levels of immunosuppressive cytokines in the micro environment, and a CD8 T-cell response and T-cell-mediated cytotoxicity. These changes are noted within days of starting therapy, correlate with tumor response, reverse with resistance, and occur in metastatic and advanced, operable disease. Enhanced PDL-1 expression by melanoma cells and increased markers of immune exhaustion, including PD-1 and TIM-1, have been identified, suggesting that the immune response is down-modulated before resistance occurs. These findings indicate that BRAF- and MEK-targeted therapies have multiple, complex, and interrelated mechanisms of action and validate the investigation of combination treatment strategies with targeted therapy and immune checkpoint inhibitors, as well as other therapies that modulate the immune microenvironment. They also lend support for clinical trials investigating preoperative and adjuvant BRAF-targeted therapy for high-risk, BRAF-mutated melanoma. Together, these studies will enhance our understanding of the mechanism of action of BRAF-targeted therapies and may identify additional opportunities to improve the outcome of patients with advanced melanoma.

CITED BY
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  2. Zhao Tian, Kong Feng-Wei, Wang Heng, Liu Dong, Wang Chun-Ying, Luo Jin-Hua, Zhang Miao, Wu Wen-Bin, A long-term survivor with esophageal melanoma and pulmonary metastasis after single-stage esophagectomy and lobectomy, Medicine, 96, 21, 2017. Crossref

  3. Wang Gan, Wang Le, Zhou Jianlong, Xu Xiaoxin, The Possible Role of PD-1 Protein in Ganoderma lucidum–Mediated Immunomodulation and Cancer Treatment, Integrative Cancer Therapies, 18, 2019. Crossref

  4. Proietti Ilaria, Skroza Nevena, Michelini Simone, Mambrin Alessandra, Balduzzi Veronica, Bernardini Nicoletta, Marchesiello Anna, Tolino Ersilia, Volpe Salvatore, Maddalena Patrizia, Di Fraia Marco, Mangino Giorgio, Romeo Giovanna, Potenza Concetta, BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions, Cancers, 12, 7, 2020. Crossref

  5. Indini Alice, Roila Fausto, Grossi Francesco, Massi Daniela, Mandalà Mario, Impact of Circulating and Tissue Biomarkers in Adjuvant and Neoadjuvant Therapy for High-Risk Melanoma: Ready for Prime Time?, American Journal of Clinical Dermatology, 22, 4, 2021. Crossref

  6. Mansfield Carol, Ndife Briana, Chen Joyce, Gallaher Kathleen, Ghate Sameer, Patient preferences for treatment of metastatic melanoma, Future Oncology, 15, 11, 2019. Crossref

  7. Berciano-Guerrero Miguel-Angel, Lavado-Valenzuela Rocío, Moya Aurelio, delaCruz-Merino Luis, Toscano Fátima, Valdivia Javier, Castellón Victoria, Henao-Carrasco Fernando, Sancho Pilar, Onieva-Zafra Juan-Luis, Navas-Delgado Ismael, Rueda-Dominguez Antonio, Perez-Ruiz Elisabeth, Alba Emilio, Genes Involved in Immune Reinduction May Constitute Biomarkers of Response for Metastatic Melanoma Patients Treated with Targeted Therapy, Biomedicines, 10, 2, 2022. Crossref

  8. Vonka Vladimír, Hirsch Ivan, Prophylactic vaccines against cancers of non-infectious origin: a dream or a real possibility?, Central European Journal of Public Health, 29, 4, 2021. Crossref

  9. Guida M., Strippoli S., Maule M., Quaglino P., Ramondetta A., Chiaron Sileni V., Antonini Cappellini G., Queirolo P., Ridolfi L., Del Vecchio M., Cocorocchio E., Di Giacomo A.M., Festino L., Merelli B., Occelli M., Brugnara S., Minisini A., Sava S., Tommasi S., De Summa S., Immune checkpoint inhibitor associated vitiligo and its impact on survival in patients with metastatic melanoma: an Italian Melanoma Intergroup study, ESMO Open, 6, 2, 2021. Crossref

  10. Guardamagna Mora, Berciano-Guerrero Miguel-Angel, Villaescusa-González Beatriz, Perez-Ruiz Elisabeth, Oliver Javier, Lavado-Valenzuela Rocío, Rueda-Dominguez Antonio, Barragán Isabel, Queipo-Ortuño María Isabel, Gut Microbiota and Therapy in Metastatic Melanoma: Focus on MAPK Pathway Inhibition, International Journal of Molecular Sciences, 23, 19, 2022. Crossref

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