CMTM6 binds to PD-L1 on the plasma membrane to promote its stability and inhibitory activity.
Major finding: CMTM6 binds to PD-L1 on the plasma membrane to promote its stability and inhibitory activity.
Concept: CMTM6 depletion reduces constitutive and IFNγ-induced PD-L1 expression in a variety of cancer cells.
Impact: CMTM6 is a potential therapeutic target to indirectly inhibit PD-L1 and overcome tumor immune evasion.
Immune checkpoint therapies targeting the PD-1–PD-L1 interaction promote the antitumor activity of tumor-specific T cells and have been approved for the treatment of multiple tumor types. However, the mechanisms by which PD-L1 expression is regulated on tumor cells remain poorly understood. In two related studies, Burr and colleagues and Mezzadra and colleagues identified the type-3 transmembrane protein CMTM6 as a critical regulator of PD-L1 using a genome-wide CRISPR/Cas9 screen in pancreatic cancer cells and a haploid genetic modifier screen, respectively. CMTM6 depletion resulted in reduced expression of PD-L1, reducing both basal expression and IFNγ-induced expression of PD-L1, in a variety of cancer cell lines, including breast, lung, pancreas, thyroid, and colorectal cancers, melanoma, and chronic myeloid leukemia, as well as in primary dendritic cells. Moreover, CMTM4 was also able to positively regulate PD-L1 expression in the absence of CMTM6, although other CMTM family proteins did not. CMTM6 does not function as a transcriptional regulator of PD-L1; instead, CMTM6 loss resulted in a rapid decay of PD-L1 protein. CMTM6 bound directly to PD-L1 on the plasma membrane and in recycling endosomes, where it was required for endocytic recycling of PD-L1. Thus, CMTM6 prevented lysosomal degradation of PD-L1 to enhance PD-L1 stability. Further, in coculture experiments, CMTM6 depletion in tumor cells enhanced T-cell activity as measured by increased cytotoxic activity and augmented secretion of proinflammatory cytokines. Collectively, these studies identify CMTM6 as a positive regulator of PD-L1 expression on tumor cells that increases its inhibitory function and suggest the potential for therapeutic targeting of CMTM6 to enhance antitumor immunity.
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