Abstract
To date, IgG in the tumor microenvironment (TME) has been considered a product of B cells and serves as an antitumor antibody. However, in this study, using a monoclonal antibody against cancer-derived IgG (Cancer-IgG), we found that cancer cells could secrete IgG into the TME. Furthermore, Cancer-IgG, which carries an abnormal sialic acid modification in the CH1 domain, directly inhibited effector T-cell proliferation and significantly promoted tumor growth by reducing CD4+ and CD8+ T-cell infiltration into tumor tissues. Mechanistic studies showed that the immunosuppressive effect of sialylated Cancer-IgG is dependent on its sialylation and binding to sialic acid-binding immunoglobulin-type lectins (Siglecs) on effector CD4+ and CD8+ T cells. Importantly, we show that several Siglecs are overexpressed on effector T cells from cancer patients, but not those from healthy donors. These findings suggest that sialylated Cancer-IgG may be a ligand for Siglecs, which may serve as potential checkpoint proteins and mediate tumor immune evasion.
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Acknowledgements
We would like to thank G. Lee (Andrology Lab, University of British Columbia Centre for Reproductive Health, Vancouver, BC V5Z 4H4, Canada) for developing RP215. We thank Y. Yu (National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University) for the human and mouse Siglec-10 plasmids. This work was supported by research grants to X. Qiu from the key support projects of the National Natural Science Foundation’s major research program (91642206), major international cooperation projects of the National Natural Science Foundation (81320108020), research institute fund of the NHC Key Laboratory of Medical Immunology, Peking University (BMU2018JDJS010), the Science Technology and Innovation Committee of Shenzhen Municipality (JCYJ20170413141047772) and nonprofit central research institute fund of the Chinese Academy of Medical Sciences (2018PT31039).
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Y.Z. and X.Q. initiated and designed the research; Z.W., Z.G., W.S., E.L., and L.X. performed the experiments and analyzed and interpreted the results; J.Z. and J.T. contributed to testing the specificity of RP215 and confirmed the epitope recognized by RP215; L.Z. and X.Y. purified SIA-CIgG; W.P. carried out the GEO database mining and analysis; X.S. performed cell sorting by flow cytometry; W.X. produced and purified RP215; Z.W., Z.G., and X.Q. wrote the paper; and L.X., H.C. and X.C. provided clinical specimens and clinical and pathological information.
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Wang, Z., Geng, Z., Shao, W. et al. Cancer-derived sialylated IgG promotes tumor immune escape by binding to Siglecs on effector T cells. Cell Mol Immunol 17, 1148–1162 (2020). https://doi.org/10.1038/s41423-019-0327-9
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DOI: https://doi.org/10.1038/s41423-019-0327-9