Post-doctoral fellow Sun Yat-sen University, Guangdong, China (People's Republic)
Abstract: The clinical efficacy of programmed cell death-1 (PD-1) blockade therapy may be limited by the inclined M2 tumor-associated macrophage (TAM)- and regulatory T cell (Treg)-dominant immunosuppressive tumor microenvironment (TME). However, factors that promote the immune repressive TME remain to be elucidated. Here, we found that apoptotic hepatocellular carcinoma (HCC)-derived apoptotic vesicles (apoVs) were increased in patient tumors following anti-PD-1 therapy, correlated with enhanced infiltration of immunosuppressive cells. Moreover, HCC-apoVs produce Lactate dehydrogenase A (LDHA) to aggravate M2high and Treghigh immunosuppressive phenotypes and aggravate liver cancer. In contrast, mesenchymal stem cell (MSC)-derived apoVs abolish glycolytic tumor metabolite-conferred immunosuppressive phenotypes. Tumor cell- and MSC-derived apoVs displayed distinct properties regulating lactate production and consumption. Mechanistically, MSC-apoVs transfer multiple factors, including miR-34c-5p and nicotinamide phosphoribosyltransferase (NAMPT), to inhibit LDHA-mediated lactate metabolism and promote NAD+ metabolism-initiated glycolysis of macrophages and CD4+ T cells. Furthermore, infused MSC-apoVs can be internalized by the immune cells in the tumor and lymphoid organs. A combination of MSC-apoVs and anti-PD-1 therapy abolishes immunosuppressive TME and potentiates antitumor immunity to boost anti-PD-1 treatment for liver cancer. Our findings reveal an apoV-mediated metabolism-directing effect that can be utilized to rescue tumor metabolite-conferred immunosuppressive TME and provide new therapeutic strategies to evoke the antitumor effect of PD-1 blockade.
Funding Source: This work was supported by grants from the National Natural Science Foundation of China (82170924 to X.K.), Pearl River Talent Recruitment Program (2019ZT08Y485, 2019QN01Y138, 2019JC01Y182 to S.S. and X.K.)
