CMTM6 maintains B cell-intrinsic membrane CD40 stability to regulate anti-tumor immunity

The essential role of B cells and B cell intrinsic molecules in tumor immunity is beginning to be recognized. Tumor cell CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) is a novel tumor immunoregulator involved in maintaining membrane levels of several important molecules, such as programmed cell death ligand 1 (PD-L1) and CD58. Host CMTM6 may also play a function in the tumor microenvironment. Here, we found that CMTM6 was highly expressed in splenic B cells and tumor-infiltrating B cells. CMTM6 deficiency resulted in impaired splenic development, germinal center B cell differentiation, memory B cell differentiation, T/B cell interaction and B cell anti-tumor immune responses. Through multi-omics data mining and B-cell agonist screening, we identified that CMTM6 interacted with CD40 and maintained CD40 membrane levels in B cells. CMTM6 cis-interacts with CD40 and inhibits ubiquitin/proteasome-mediated CD40 degradation. CMTM6 deficiency led to impaired CD40 signaling-mediated B cell activation, survival, proliferation, differentiation and T/B cell interaction. In vivo, CMTM6 deficiency leads to a significant decrease in the anti-tumor activity of immune checkpoint blockade (ICB) therapy and B cell-dependent CD40 agonists. Collectively, B-cell intrinsic CMTM6 maintains B cell CD40 levels and signaling to promote B cell function and anti-tumor immunity.