CMTM6 and CMTM4 as two novel regulators of PD-L1 modulate the tumor microenvironment

Abstract

The tumor microenvironment (TME) plays crucial roles in regulating tumor occurrence, progress, metastasis and drug resistance. However, it remains largely elusive how the components of TME are regulated to govern its functions in tumor biology. Here, we discussed how the two novel functional proteins, chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing 6 (CMTM6) and CMTM4, which involved in the post-translational regulation of PD-L1, modulate the TME functions. The roles of CMTM6 and CMTM4 in regulating TME components, including immune cells and tumor cells themselves were discussed in this review. The potential clinical applications of CMTM6 and CMTM4 as biomarkers to predict therapy efficacy and as new or combined immunotherapy targets are also highlighted. Finally, the current hot topics for the biological function of CMTM6/4 and several significant research directions for CMTM6/4 are also briefly summarized in the review.

Keywords: CMTM4; CMTM6; CTL; M2 macrophage; MDSC; PD-L1; TME; Treg.

Figure 1

Mechanisms of CMTM6 and CMTM4 in regulating the function of the immune cells in TME. (A) CMTM6 protein can stabilize the PD-L1 protein on tumor cell, and this function is shared by CMTM4. CMTM6 co-localizes with PD-L1 at the plasma membrane and in recycling endosomes, where it inhibits PD-L1 being targeted for lysosome-mediated degradation. Moreover, CMTM6 inhibits the ubiquitination of PD-L1. CMTM6/4 enhancedPD-L1-mediated T cell suppression through the above pathways, as indicated by decreased secretion of perforin, TNF-α and IFN-γ.(B) CMTM6 promotes M2 macrophage polarization through exosome shuttling by activating ERK1/2 signaling in M0, whereas it inhibits M1 macrophage polarization. It is mainly manifested by the up-regulation of M2-specific markers such as CD163 and IL-10 and the down-regulation of M1-specific markers such as CD80, CD86, TNF-a and IL-12p40.

Figure 2

Effects and mechanisms of CMTM6 and CMTM4 in regulating the function of tumor and endothelial cells in TME. (A) CMTM6 promotes tumor proliferation, migration and invasion by activating the mTOR pathway. (B) CMTM6 maintains stem cell-like properties through affect Wnt/β-catenin signaling pathway, mainly manifested by elevated expression of several CSC-related markers such as CD44, ALDH and BMI1. (C) CMTM6 induces epithelial-mesenchymal transition (EMT) by stabilizing vimentin, which behaved as the E-cadherin decreased. (D) CMTM4 positively affected CSC-like properties via the AKT pathway, mainly manifested by significantly elevated expression of CSC markers (CD44, ALDH1, BMI1, and SOX2). (E) CMTM4 promotes EMT through positive regulation of SLUG. (F) CMTM4 plays an important role in regulating angiogenesis by enhancing the bio-availability of VE-cadherin at cell-cell adherens junctions and promoting endothelial barrier function.