For example, CDK4/6 inhibition restricts optimal T cells expansion, and when used in combination with BRAF/MEK-targeted therapies, depletes immune-potentiating myeloid subsets from the tumor microenvironment. However, in some contexts, the specific immunomodulatory effects of CDK4/6i may impinge on anti-tumor immunity. Among the most notable effects, CDK4/6 inhibition induces transcriptional reprogramming in both tumor cells and immune cells to enhance tumor cell immunogenicity, promote an immune-rich tumor microenvironment, and skew T cell differentiation into a stem-like phenotype that is more amenable to immune checkpoint inhibition. In recent studies, we and others have proven the immunomodulatory effects of CDK4/6i to be multifaceted and complex. Recent revelations into the immunotherapeutic activity of CDK4/6i, therefore, have significant implications for the utility of these agents as melanoma therapies. Melanoma is a highly immunogenic cancer, and has always been situated at the forefront of cancer immunotherapy development. While currently approved to treat hormone receptor-positive breast cancer, these inhibitors are under investigation in clinical trials as treatments for a range of cancer types, including melanoma. In this review, we present the current knowledge on the immunomodulatory functions of BRAF/MEKi as well as the non-intended effects of ICI and discuss the potential synergistic effects of ICI and MAPK inhibitors in melanoma treatment.ĬDK4/6 inhibitors (CDK4/6i) were developed as a cancer therapeutic on the basis of their tumor-intrinsic cytostatic potential, but have since demonstrated profound activity as immunomodulatory agents. Next to the antiproliferative effects of BRAF/MEKi, accumulating preclinical evidence suggests that BRAF/MEKi exert immunomodulatory functions such as paradoxical ERK activation as well as additional effects in non-tumor cells. Patients with a BRAF mutation are regularly treated with a combination of BRAF and MEK (MAPK/ERK kinase) inhibitors. In about half of all melanoma patients, tumor growth is driven by gain-of-function mutations of BRAF (v-rat fibrosarcoma (Raf) murine sarcoma viral oncogene homolog B), which results in constitutive ERK activation. The advent of mitogen-activated protein kinase (MAPK) inhibitors that directly inhibit tumor growth and of immune checkpoint inhibitors (ICI) that boost effector T cell responses have strongly improved the treatment of metastatic melanoma. The increase in tumor-infiltrating lymphocytes induced by treatment with BRAF inhibitors provides strong support for conducting trials that combine BRAF inhibitors with immunotherapy in the hope of prolonging clinical responses.

Increased intratumoral CD8(+) lymphocyte expression was correlated with a reduction in tumor size and an increase in necrosis in posttreatment biopsies (r = -0.793, ρ = 0.011 and r = 0.761, ρ = 0.004, respectively). There was a correlation between the degree of tumor infiltration by CD8(+) and Granzyme B-expressing lymphocytes in post-BRAF inhibitor-treated biopsies (r = 0.690 and ρ = 0.013). Tumor infiltration by CD4(+) and CD8(+) lymphocytes increased markedly following BRAF inhibitor treatment (both ρ = 0.015).

Immunohistochemical staining was carried out on the biopsies using specific antibodies for CD8, CD4, CD20, CD1a, and Granzyme B. Thirty-seven tumor biopsies were collected from 15 patients with unresectable American Joint Committee on Cancer stage III or IV melanoma immediately before and approximately 7 days after the commencement of BRAF inhibitor treatment and at the time of tumor progression. To evaluate the effects of treatment with the potent mutant BRAF inhibitors GSK2118436 or vemurafenib (PLX4720) on immune responses to metastatic melanoma in tissues taken before and after treatment.

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