Abstract
Personalized immunotherapy targeting tumor-specific antigens (TSAs) could generate efficient and safe antitumor immune response without damaging normal tissues. Although neoantigen vaccines have shown therapeutic effect in clinic trials, precise prediction of neoantigens from tumor mutations is still challenging. The host antitumor immune response selects and activates T cells recognizing tumor antigens. Hence, T cells engineered with T-cell receptors (TCRs) from these naturally occurring tumor antigen-specific T (Tas) cells in a patient will target personal TSAs in his/her tumor. To establish such a personalized TCR-T cell therapy, we comprehensively characterized T cells in tumor and its adjacent tissues by single-cell mRNA sequencing (scRNA-seq), TCR sequencing (TCR-seq) and in vitro neoantigen stimulation. Compared to bystander T cells circulating among tissues, Tas cells were characterized by tumor enrichment, tumor-specific clonal expansion and neoantigen specificity. We found that CXCL13 is a unique marker for both CD4+ and CD8+ Tas cells. Importantly, TCR-T cells expressing TCRs from Tas cells showed significant therapeutic effects on autologous patient-derived xenograft (PDX) tumors. Intratumoral Tas cell levels measured by CXCL13 expression precisely predicted the response to immune checkpoint blockade, indicating a critical role of Tas cells in the antitumor immunity. We further identified CD200 and ENTPD1 as surface markers for CD4+ and CD8+ Tas cells respectively, which enabled the isolation of Tas cells from tumor by Fluorescence Activating Cell Sorter (FACS) sorting. Overall, our results suggest that TCR-T cells engineered with Tas TCRs are a promising agent for personalized immunotherapy, and intratumoral Tas cell levels determine the response to immunotherapy.
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Data availability
The raw data files were deposited in the Genome Sequencing Archive of the National Genomics Data Center with the accession number of PRJCA003922.
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Acknowledgements
This study is supported by grants from the National Key R&D Program of China (2016YFA0500304), the National Nature Science Foundation of China (NSFC) (81773052, 81572806, 81802854, 81802853), the Guangzhou Science Technology and Innovation Commission (201607020038), the Natural Science Foundation of Guangdong Province (2017A030308007), the Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S638) and the Leading Talents Program of Guangdong Province (2016LJ06S464).
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P.Z. conceived and supervised the project; P.Z. and J.H. drafted the manuscript; P.D., X.Z., W.L. and Z.Z. contributed to the project design and extensive discussions. J.H., Z.L., X.Xiong, K.Y. and H.Y. performed the scRNA-seq experiments and second-generation sequencing; Z.Z., X.L., K.Z. and X.D. performed data analysis; H.Y., D.L., S.L., X.W., P.D. and X.Z. supervised the collection of patient samples. L.F. and S.L. performed IHC staining and analysis. Z.L., S.L. C.B., X.L., H.L. and X.Xiong generated TCR-T cells, LCLs and in vitro tumor antigen stimulation. J.H., X.Xiong and H.Y. sorted Tas cells from patient tumors. S.C., J.H. and W.L. established PDX tumor models and performed the therapeutic experiments. X.Xia, T.K. and Z.Z. provided advice of experiments and edited the manuscript.
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C.B., X.L., H.L. are current employee of FineImmune. The other authors declare that they have no competing interests.
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He, J., Xiong, X., Yang, H. et al. Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response. Cell Res 32, 530–542 (2022). https://doi.org/10.1038/s41422-022-00627-9
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DOI: https://doi.org/10.1038/s41422-022-00627-9
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