CMTM6/PD-L1-targeted AAV promotes anti-tumor immune responses and chemotherapy responsiveness.

Chemotherapy is one of the important clinical treatments for malignant tumors, but primary or acquired chemotherapy resistance significantly limits patient benefits. Programmed death ligand 1 (PD-L1) has been reported to be regulated by chemotherapy and to contribute to chemotherapy resistance. However, as a novel regulatory molecule of PD-L1, the relationship between CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) and chemotherapy resistance remains understudied. Here, we found that tumor CMTM6 and PD-L1 were upregulated by chemotherapy in clinical cancer patients, in vitro human or mouse tumor models, and in vivo mouse tumor models. PI3K-mTOR was the potential mechanism underlying this effect. CMTM6 deficiency could still reduce chemotherapy-induced tumor PD-L1 expression. And CMTM6 could promote tumor cell resistance to chemotherapy-induced apoptosis and growth arrest, which may be associated with p53. In vivo, both tumor and host CMTM6 and PD-L1 could promote resistance to chemotherapy, and tumor and host CMTM6 knockout could promoted antitumor immune responses during chemotherapy. Moreover, we developed and evaluated the antitumor effects of CMTM6&PD-L1-targeting adeno-associated virus (AAV), which effectively mobilized antitumor immunity and could be combined with chemotherapy. Our findings reveal that both tumor- and host-derived CMTM6 and PD-L1 are regulatory molecules of chemotherapy resistance and can serve as therapeutic targets for combination therapy with chemotherapy.