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Although the pre‐clinical study of chimeric antigen receptor (CAR)‐natural killer (NK) cell was effective against various tumours, immunosuppression mediated by tumour microenvironment hampers their application and several efforts have been explored to improve their effect in combating solid tumours. Glypican 3 (GPC3) is a promising target for hepatocellular carcinoma (HCC), and CAR‐T cells targeting GPC3 have been tested in clinical trials. Based on an affinity‐enhanced antibody (hYP7) targeting GPC3, we constructed GPC3‐CAR‐NK cells to explore their potential function in the treatment of HCC. We found that patients with HCC secreted high levels of soluble programmed death‐ligand 1 (sPD‐L1), which inhibits the function of CAR‐NK cells targeting GPC3. In addition, we combined high‐affinity sPD‐L1 variant (L3C7c‐Fc) with GPC3‐CAR‐NK cells to solve the problem of GPC3‐CAR‐NK inhibition. Our studies demonstrated that L3C7c‐Fc could enhance the therapeutic effect of CAR‐NK cells by reversing the suppression of sPD‐L1, which provides the experimental evidence for the subsequent development of HCC immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Background: A major challenge in the development of effective cancer immunotherapy is the ability of tumors and their microenvironment to suppress immune cells through immunosuppressive cells such as myeloid -derived suppressor cells and regulatory T cells. We previously demonstrated that Plasmodium infection promotes innate and adaptive immunity against cancer in a murine Lewis lung cancer model but its effects on immunosuppressive cells in the tumor microenvironment are unknown. Methods: Whole Tumors and tumor-derived sorted cells from tumor-bearing mice treated with or without plasmodium infected red blood cells were harvested 17 days post tumor implantation and analyzed using QPCR, western blotting, flow cytometry, and functional assays. Differences between groups were analyzed for statistical significance using Student's t-test. Results: Here we found that Plasmodium infection significantly reduced the proportions of MDSCs and Tregs in the lung tumor tissues of the treated mice by downregulating their recruiting molecules and blocking cellular activation pathways. Importantly, CD8+ T cells isolated from the tumors of Plasmodium-treated mice exhibited significantly higher levels of granzyme B and perforin and remarkably lower levels of PD-1. Conclusion: We reveal for the first time, the effects of Plasmodium infection on the expansion and activation of MDSCs and Tregs with a consequent elevation of CD8+T cell-mediated cytotoxicity within the tumor microenvironment and hold great promise for the development of effective immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]