RESUMEN
Major advances have been made in melanoma treatment with the use of molecularly targeted therapies and immunotherapies, and numerous regimens are now approved by the US Food and Drug Administration for patients with stage IV disease. However, therapeutic resistance remains an issue to both classes of agents, and reliable biomarkers of therapeutic response and resistance are lacking. Mechanistic insights are being gained through preclinical studies and translational research, offering potential strategies to enhance responses and survival in treated patients. A comprehensive understanding of the immune effects of common mutations at play in melanoma is critical, as is an appreciation of the molecular mechanisms contributing to therapeutic resistance to immunotherapy. These mechanisms and the interplay between them are discussed herein. Cancer 2017;123:2130-42. © 2017 American Cancer Society.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Melanoma/inmunología , Fosfohidrolasa PTEN/inmunología , Proteínas Proto-Oncogénicas B-raf/inmunología , Neoplasias Cutáneas/inmunología , Escape del Tumor/inmunología , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antígeno CTLA-4/antagonistas & inhibidores , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/inmunología , Humanos , Imidazoles/administración & dosificación , Inmunoterapia , Indoles/administración & dosificación , Ipilimumab , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 1/genética , Melanoma/tratamiento farmacológico , Melanoma/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Terapia Molecular Dirigida , Mutación , Nivolumab , Oximas/administración & dosificación , Fosfohidrolasa PTEN/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Sulfonamidas/administración & dosificación , Escape del Tumor/genética , Vemurafenib , Vía de Señalización Wnt/genética , Vía de Señalización Wnt/inmunologíaRESUMEN
Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to antiprogrammed cell death 1 (antiPD-1)based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γpositive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.