BRAF inhibition curtails IFN‐gamma‐inducible PD‐L1 expression and upregulates the immunoregulatory protein galectin‐1 in melanoma cells

Abstract

Although melanoma is considered one of the most immunogenic malignancies, spontaneous T‐cell responses to melanoma antigens are ineffective due to tumor cell‐intrinsic or microenvironment‐driven immune evasion mechanisms. For example, oncogenic BRAF V600E mutation in melanoma cells fosters tumor immune escape by modulating cell immunogenicity and microenvironment composition. BRAF inhibition has been shown to increase melanoma cell immunogenicity, but these effects are transient and long‐term responses are uncommon. For these reasons, we aimed to further characterize the role of BRAF‐V600E mutation in the modulation of PD‐L1, a known immunoregulatory molecule, and galectin‐1 (Gal‐1), a potent immunoregulatory lectin involved in melanoma immune privilege. We report herein that vemurafenib downregulates IFN‐γ‐induced PD‐L1 expression by interfering with STAT1 activity and by decreasing PD‐L1 protein translation. Surprisingly, melanoma cells exposed to vemurafenib expressed higher levels of Gal‐1. In coculture experiments, A375 melanoma cells pretreated with vemurafenib induced apoptosis of interacting Jurkat T cells, whereas genetic inhibition of Gal‐1 in these cells restored the viability of cocultured T lymphocytes, indicating that Gal‐1 contributes to tumor immune escape. Importantly, Gal‐1 plasma concentration increased in patients progressing on BRAF/MEK inhibitor treatment, but remained stable in responding patients. Taken together, these results suggest a two‐faceted nature of BRAF inhibition‐associated immunomodulatory effects: an early immunostimulatory activity, mediated at least in part by decreased PD‐L1 expression, and a delayed immunosuppressive effect associated with Gal‐1 induction. Importantly, our observations suggest that Gal‐1 might be utilized as a potential biomarker and a putative therapeutic target in melanoma patients.

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

“…In the tumor cell, this reversion to a low immunogenic state is caused by induced expression of programmed cell death ligand-1 (PD-L1) [ 165 , 166 , 167 , 168 , 169 ], increased expression of the immunoregulatory protein Galactin-1 [ 170 ], and increased expression of CD47, an immunoregulatory cell marker, on tumor cells, leading to reduced killing by cytotoxic T-cells and macrophages [ 133 ]. BRAF inhibitor-resistant tumor cells also show reduced expression of target antigens [ 164 ], and increased production of IL-10 [ 33 ].…”

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

“…Given the cross-talk between MEK/ERK1/2 and mTOR pathways, these observations might in fact have a common explanation. As ERK1/2 phosphorylates p90RSK kinase, which activates mTOR [38][39][40] , the inhibition of ERK1/2 might also lead to a decreased mTOR activity. Although our studies strongly implicate the MEK/ERK1/2 pathway in SYK-inhibitor-induced differentiation, this cascade likely plays a broader role in mediating responses to SYK inhibitor.…”

Nanomaterials Enhance the Immunomodulatory Effect of Molecular Targeted Therapy

“…A recent study showed that vemurafenib played an immune-activating role in the early stage of BRAF-V600E mutant melanoma by downregulating the expression of PD-L1 and promoted the immune escape of tumor cells in the late stage by inducing the expression of galectin-1. 133 Moreover, some molecular targeted drugs target multiple kinases and can affect a variety of immune cells. Therefore, clarifying the specific mechanism of molecular targeted drugs in regulating immunity can provide a sufficient basis for their combination with immunotherapy and contribute to the design of more reasonable and effective combination therapy strategies.…”