BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma

By Dennie T. Frederick, A. Piris, Alexandria P. Cogdill, Z. Cooper, C. Lezcano, Cristina R. Ferrone, D. Mitra, Andrea Boni, Lindsay P. Newton, Chengwen Liu and 11 more. Clinical Cancer Research, 2013

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Purpose: To evaluate the effects of BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma. Experimental Design: Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10 to 14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition (dabrafenib + trametinib) and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T-cell markers, and immunomodulatory cytokines. Results: Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T-cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines [interleukin (IL)-6 and IL-8] and an increase in markers of T-cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 was increased on treatment. A decrease in melanoma antigen expression and CD8 T-cell infiltrate was noted at time of progression on BRAF inhibitor alone and was reversed with combined BRAF and MEK inhibition. Conclusions: Together, these data suggest that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T-cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma. Clin Cancer Res; 19(5); 1225–31. ©2013 AACR.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/3da20df7495a7262b82e5746197d26616746f614

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Citations in the corpus

Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. (2013, background): “…antigen (which is responsive to 5-fluorouracil), various cancer testis antigens (which are upregulated by 5-aza-20deoxycytidine and g irradiation), and melanoma-associated antigens (which respond to the BRAF inhibitor vemurafenib) (Chen and Emens, 2013; Frederick et al., 2013; Sharma et al., 2011).”
Revisiting the hallmarks of cancer. (2017, neutral): “[187] Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, Mitra D, Boni A, Newton LP and Liu C.”
Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity (2015, background): “Notably, our findings that COX-2 expression depends on active RAF/MEK signaling suggests that reduced production of PGE2 by melanoma cells may contribute to the immune-dependent anti-cancer activity elicited by BRAF inhibitors (Frederick et al., 2013; Knight et al., 2013).”
Immune Checkpoint Targeting in Cancer Therapy: Towards Combination Strategies with Curative Potential (2015, background): “Vemurafenib, an FDA-approved BRAF inhibitor used for the treatment of melanoma, has been shown to increase expression of tumor antigens and MHC molecules (Frederick et al., 2013), increasing the sensitivity of the tumor cells to immune attack.”
Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. (2015, background): “However, this is generally accompanied by an increase in the expression of T cell exhaustion markers like PD-1 and hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3) (Frederick et al., 2013; Wilmott et al., 2012), an effect that is partially reversed by MAPK inhibitors (Kakavand et ”