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

SUMMARY Highlights B cells participate in anti-tumor immunity by influencing the intratumoral infiltration and function of T cells; CMTM6 cis-interacts with CD40 and inhibits ubiquitin/proteasome-mediated CD40 degradation to maintain CD40 cell membrane levels; Loss of B cell-intrinsic CMTM6 significantly reduces CD40 signaling-mediated B cell activation, survival, differentiation, T/B cell interaction and anti-tumor immunity; B cell-intrinsic CMTM6 deficiency leads to a significant reduction in the anti-tumor activity CD40 agonists and ICB therapy. In Brief Long et al. demonstrate that B-cell intrinsic CMTM6 regulates CD40 signaling and function via maintaining the cell membrane level of B-cell CD40 through ubiquitin-proteasome pathway inhibition, thereby affecting B cell function, anti-tumor B-cell immunity and the efficacy of CD40 agonist and ICB therapy. The essential role of B cells and B cell intrinsic molecules in tumor immunity is beginning to be recognized. Tumor cell CMTM6 is a novel tumor immunoregulator involved in maintaining membrane levels of several important molecules, such as 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 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. Competing Interest Statement The authors have declared no competing interest. Footnotes 1. CMTM6/CD40 interaction studies 2. CD40 signaling dependence studies 3. Manuscript writing adjustments