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.
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Data Availability
The analyzed datasets generated during this study are available from the corresponding author upon reasonable request. The transcriptomic data are available in Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/) under the accession codes GSE223856.
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Funding
This work was supported by National Key R&D Program of China (2020YFA0509400 and 2019YFA0110300), National Natural Science Foundation of China (82150117, 82071745 and 82101329), Science and Technology Program of Guangzhou (202002030069), Guangdong project (2019QN01Y212), Guangdong Basic and Applied Basic Research Foundation of China (2021A1515012620), Guangzhou Science and Technology Project of China (202201010993 and 105068559019) and a Grant from MOE Key Laboratory of Gene Function and Regulation.
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J.C. and Y.Y.L. wrote the original manuscript. Y.Y.L. and X.Y.W. conceived and conducted most of experiments and data curation. Y.L. participated in the data analysis of the clinical samples. X.M.W., J.L., Y.Z.W. and H.H. assisted with some animal experiments. J.C. and W.Y. supervised the research and authored the final manuscript. All authors reviewed the manuscript. We thank Figdraw (https://www.figdraw.com) for expert assistance in the pattern drawing.
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Yi-yi Li and Xin-yu Wang contributed equally to this work.
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Li, Yy., Wang, Xy., Li, Y. et al. Targeting CD43 optimizes cancer immunotherapy through reinvigorating antitumor immune response in colorectal cancer. Cell Oncol. 46, 777–791 (2023). https://doi.org/10.1007/s13402-023-00794-w
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DOI: https://doi.org/10.1007/s13402-023-00794-w