Abstract：
Immunotherapy, especially immune checkpoint inhibitors, has revolutionized clinical practice within the last decade. However, primary and secondary resistance to immunotherapy is common in patients with diverse types of cancer. It is well-acknowledged that tumor cells can facilitate the formation of immunosuppressive microenvironments via metabolism reprogramming, and lactic acid, the metabolite of glycolysis, is a significant contributor. SLC16A3 (also named as MCT4) is a transporter mediating lactic acid efflux. In this study, we investigated the role of glycolysis in immunotherapy resistance and aimed to improve the immunotherapy effects via Slc16a3 inhibition. Bioinformatical analysis revealed that the expression of glycolysis-related genes correlated with less CD8+ T cell infiltration and increased myeloid-derived suppressor cells (MDSC) enrichment. We found that high glycolytic activity in tumor cells adversely affected the antitumor immune responses and efficacy of immunotherapy and radiotherapy. As the transporter of lactic acid, SLC16A3 is highly expressed in glycolytic B16-F10 (RRID: CVCL_0159) cells, as well as human non-small cell lung carcinoma. We validated that Slc16a3 expression in tumor cells negatively correlated with anti-PD-1 efficiency. Overexpression of Slc16a3 in tumor cells promoted lactic acid production and efflux, and reduced tumor response to anti-PD-1 inhibitors by inhibiting CD8+ T cell function. Genetic and pharmacological inhibition of Slc16a3 dramatically reduced the glycolytic activity and lactic acid production in tumor cells, and ameliorated the immunosuppressive tumor microenvironments (TMEs), leading to boosted antitumor effects via anti-PD-1 blockade. Our study therefore demonstrates that tumor cell-intrinsic SLC16A3 may be a potential target to reverse tumor resistance to immunotherapy.
摘要：
免疫疗法,尤其是免疫检查点抑制剂，在过去的十年里彻底改变了临床实践。然而,对免疫疗法的原发性和继发性耐药性在患有不同类型癌症的患者中很常见.众所周知，肿瘤细胞可以通过代谢重编程促进免疫抑制微环境的形成，还有乳酸,糖酵解的代谢产物，是一个重要的贡献者。SLC16A3（也称为MCT4）是介导乳酸流出的转运蛋白。在这项研究中,我们研究了糖酵解在免疫治疗抵抗中的作用,旨在通过Slc16a3抑制改善免疫治疗效果.生物信息学分析显示，糖酵解相关基因的表达与CD8T细胞浸润减少和髓源性抑制细胞（MDSC）富集增加相关。我们发现，肿瘤细胞中的高糖酵解活性会不利地影响抗肿瘤免疫反应以及免疫疗法和放射疗法的功效。作为乳酸的转运蛋白,SLC16A3在糖酵解B16-F10(RRID:CVCL_0159)细胞中高表达,以及人类非小细胞肺癌。我们验证了Slc16a3在肿瘤细胞中的表达与抗PD-1效率呈负相关。Slc16a3在肿瘤细胞中的过表达促进乳酸的产生和流出,并通过抑制CD8+T细胞功能降低肿瘤对抗PD-1抑制剂的反应。Slc16a3的遗传和药理抑制显着降低了肿瘤细胞中的糖酵解活性和乳酸的产生，并改善了免疫抑制肿瘤微环境（TME），导致通过抗PD-1阻断增强的抗肿瘤作用。因此，我们的研究表明，肿瘤细胞固有的SLC16A3可能是逆转肿瘤对免疫疗法耐药性的潜在靶标。
