A recycling program that keeps PD-L1 out of the cancer cell's junkyard

PD-L1/PD-1 interactions play an important role in maintaining peripheral immune tolerance. In the setting of chronic viral infection and neoplasia, persistent PD-L1/PD-1 signaling can have pathologic consequences by promoting immune exhaustion. PD-L1 is well known to be up-regulated in response to inflammatory cytokines, notably interferon-γ (IFN-γ). To date, genes involved in regulating constitutive or interferon-inducible PD-L1 expression have not been comprehensively evaluated.

To address this question, Burr et al. used a CRISPR/Cas9 loss-of-function screen targeting over 20,000 protein-coding genes in a human pancreatic cancer cell line. Not surprisingly, the majority of genes identified by the screen included known regulators of interferon-inducible PD-L1 expression, namely the IFN-γ receptor subunits (INFNGR1, IFNGR2) and JAK/STAT members (JAK1, JAK2, STAT1). The only additional gene recovered by the screen was a gene that encodes plasma membrane protein, CKLF-like MARVEL transmembrane domain containing protein 6 (CMTM6). The functions of CMTM6 have not been previously characterized. Deletion of CMTM6 consistently led to a reduction in basal and interferon-inducible PD-L1 protein expression in multiple cell lines. CMTM6 was also independently reported as a regulator of PD-L1 expression in a companion paper by Mezzadra et al. Deletion of CMTM6 did not affect levels of PD-L1 messenger RNA but decreased levels of PD-L1 protein present on the cell surface. Consistent with this finding, CMTM6-deficient tumor cells showed impaired recycling of endocytosed PD-L1 protein, suggesting that CMTM6 may protect PD-L1 from lysosomal degradation. Further, the authors demonstrated a function for CMTM6 in antitumor immunity. CMTM6-deficient tumor cells were more susceptible to killing by antigen-specific cytotoxic T cells in vitro and were associated with longer overall survival in a murine transplantable melanoma model.

Several interesting questions that were unexplored in the study include whether CMTM6 is dysregulated in human cancers and what toxicities might be associated with systemic CMTM6 inhibition. The latter of these questions is particularly relevant to the future evaluation of CMTM6 as a therapeutic target to counteract PD-L1–dependent immune escape in tumors.