Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.

BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (∼6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8(+) T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten(-/-) syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8(+) T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8(+) T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy.

Cooper ZA ，Juneja VR ，Sage PT ，Frederick DT ，Piris A ，Mitra D ，Lo JA ，Hodi FS ，Freeman GJ ，Bosenberg MW ，McMahon M ，Flaherty KT ，Fisher DE ，Sharpe AH ，Wargo JA ... -  《-》

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors.

Knight DA ，Ngiow SF ，Li M ，Parmenter T ，Mok S ，Cass A ，Haynes NM ，Kinross K ，Yagita H ，Koya RC ，Graeber TG ，Ribas A ，McArthur GA ，Smyth MJ ... -  《-》

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

To evaluate the effects of BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma. 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. 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. 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.

Frederick DT ，Piris A ，Cogdill AP ，Cooper ZA ，Lezcano C ，Ferrone CR ，Mitra D ，Boni A ，Newton LP ，Liu C ，Peng W ，Sullivan RJ ，Lawrence DP ，Hodi FS ，Overwijk WW ，Lizée G ，Murphy GF ，Hwu P ，Flaherty KT ，Fisher DE ，Wargo JA ... -  《-》

Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition.

Mok S ，Tsoi J ，Koya RC ，Hu-Lieskovan S ，West BL ，Bollag G ，Graeber TG ，Ribas A ... -  《BMC CANCER》

Interaction of molecular alterations with immune response in melanoma.

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.

Szczepaniak Sloane RA ，Gopalakrishnan V ，Reddy SM ，Zhang X ，Reuben A ，Wargo JA ... -  《-》