Targeting CD43 optimizes cancer immunotherapy through reinvigorating antitumor immune response in colorectal cancer

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Abstract
Purpose Colorectal cancer (CRC) is one of the most common malignancies worldwide, with dramatically increasing incidence and mortality for decades. However, current therapeutic strategies for CRC, including chemotherapies and immunotherapies, have only demonstrated limited efficacy. Here, we report a novel immune molecule, CD43, that can regulate the tumor immune microenvironment (TIME) and serves as a promising target for CRC immunotherapy. Methods The correlation of CD43 expression with CRC patient prognosis was revealed by public data analysis. CD43 knockout (KO) CRC cell lines were generated by CRISPR-Cas9 technology, and a syngenetic murine CRC model was established to investigate the in vivo function of CD43. The TIME was analyzed via immunohistochemical staining, flow cytometry and RNA-seq. Immune functions were investigated by depletion of immune subsets in vivo and T-cell functional assays in vitro, including T-cell priming, cytotoxicity, and chemotaxis experiments. Results In this study, we found that high expression of CD43 was correlated with poor survival of CRC patients and the limited infiltration of CD8+ T cells in human CRC tissues. Importantly, CD43 expressed on tumor cells, rather than host cells, promoted tumor progression in a syngeneic tumor model. Loss of CD43 facilitated the infiltration of immune cells and immunological memory in the TIME of CRC tumors. Mechanistically, the protumor effect of CD43 depends on T cells, thereby attenuating T-cell-mediated cytotoxicity and cDC1-mediated antigen-specific T-cell activation. Moreover, targeting CD43 synergistically improved PD-L1 blockade immunotherapy for CRC. Conclusion Our findings revealed that targeting tumor-intrinsic CD43 could activate the antitumor immune response and provide particular value for optimized cancer immunotherapy by regulating the TIME in CRC patients.
Funding Information
  • Guangdong Basic and Applied Basic Research Foundation of China (2021A1515012620)
  • Guangzhou Science and Technology Project of China (202201010993, 105068559019, 202201010993)
  • Grant from MOE Key Laboratory of Gene Function and Regulation
  • National Natural Science Foundation of China (82101329, 82150117)
  • National Key Research and Development Program of China (2020YFA0509400)
  • Guangdong Project (2019QN01Y212)

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