Abstract
Cancer is one of the most significant causes of death in dogs. Antibody drugs targeting the PD-1/PD-L1 axis represent a promising immunotherapy for both human and canine cancers. However, the regulation mechanisms of PD-L1 expression in canine cancers require further investigation to better understand the resistance mechanisms to anti-PD-L1 therapy. Recent reports have shown that CMTM6 and CMTM4 are critical regulators of PD-L1 protein expression in human cancer cells. By preventing PD-L1 from lysosome-mediated degradation, CMTM6 maintains PD-L1 expression on the cell surface. However, the literature has not reported on CMTM6 and CMTM4 in dogs, and their functions are completely unknown. To reveal a regulation mechanism of PD-L1 in canine cancers, this study firstly identified the gene sequences of CMTM6 and CMTM4. Then, the expression analysis of these proteins was performed by immunohistochemistry. Furthermore, the functions of CMTM6 and CMTM4 in regulating PD-L1 expression were examined by gene knockdown of CMTM6 and CMTM4. Canine CMTM6 and CMTM4 displayed high amino acid sequence identities compared with those of humans and mice. An immunohistochemical analysis using cross-reactive antibodies revealed that canine malignant melanoma and osteosarcoma express CMTM6, CMTM4, and PD-L1 simultaneously. Gene knockdown of CMTM6 and CMTM4 with RNA interference significantly reduced the cell surface expression of PD-L1 in a canine cell line. These results suggest that CMTM6 and CMTM4 are regulators of PD-L1 expression in canine cancers and could serve as potential therapeutic targets to enhance antitumor immunity.
Highlights
The importance of cancer treatment has recently been highlighted in dogs because tumorassociated deaths comprise approximately 40% of canine mortality [1]
Anti-programmed death ligand 1 (PD-L1) antibody has been developed for canine cancer treatment, and its promising efficacy against malignant melanoma and undifferentiated sarcoma was reported in a pilot clinical study [14]
The MARVEL domain was predicted in canine CMTM6 and CMTM4, suggesting that functions of these genes are conserved in dogs
Summary
The importance of cancer treatment has recently been highlighted in dogs because tumorassociated deaths comprise approximately 40% of canine mortality [1]. Surgery, chemotherapy, and radiation have been the main treatment modalities for canine cancers. A ligand for PD-1, programmed death ligand 1 (PD-L1), can be expressed on tumor cells; the PD-1/PD-L1 axis is involved in the immune evasion of tumor cells [6, 7]. This suppression is reversible, and the blockade of the PD-1/PD-L1 pathway using anti-PD-1 or PD-L1 antibodies can restore the effector functions of T cells including the capacities for cell proliferation and cytokine secretion [8, 9]. Antibody therapies targeting the PD1/PD-L1 pathway showed tolerable safety profiles and promising antitumor activities [10, 11], and these antibody drugs are widely used to treat various cancers in clinics
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