Dataset Information

Neoantigen-specific CD4⁺ T cells in human melanoma have diverse differentiation states and correlate with CD8⁺ T cell, macrophage, and B cell function.

ABSTRACT: CD4⁺ T cells that recognize tumor antigens are required for immune checkpoint inhibitor efficacy in murine models, but their contributions in human cancer are unclear. We used single-cell RNA sequencing and T cell receptor sequences to identify signatures and functional correlates of tumor-specific CD4⁺ T cells infiltrating human melanoma. Conventional CD4⁺ T cells that recognize tumor neoantigens express CXCL13 and are subdivided into clusters expressing memory and T follicular helper markers, and those expressing cytolytic markers, inhibitory receptors, and IFN-γ. The frequency of CXCL13⁺ CD4⁺ T cells in the tumor correlated with the transcriptional states of CD8⁺ T cells and macrophages, maturation of B cells, and patient survival. Similar correlations were observed in a breast cancer cohort. These results identify phenotypes and functional correlates of tumor-specific CD4⁺ T cells in melanoma and suggest the possibility of using such cells to modify the tumor microenvironment.

SUBMITTER: Veatch JR

PROVIDER: S-EPMC9011147 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Neoantigen-specific CD4+ T cells in human melanoma have diverse differentiation states and correlate with CD8+ T cell, macrophage, and B cell function.

Veatch Joshua R JR Lee Sylvia M SM Shasha Carolyn C Singhi Naina N Szeto Julia L JL Moshiri Ata S AS Kim Teresa S TS Smythe Kimberly K Kong Paul P Fitzgibbon Matthew M Jesernig Brenda B Bhatia Shailender S Tykodi Scott S SS Hall Evan T ET Byrd David R DR Thompson John A JA Pillarisetty Venu G VG Duhen Thomas T McGarry Houghton A A Newell Evan E Gottardo Raphael R Riddell Stanley R SR

Cancer cell 20220401 4

CD4+ T cells that recognize tumor antigens are required for immune checkpoint inhibitor efficacy in murine models, but their contributions in human cancer are unclear. We used single-cell RNA sequencing and T cell receptor sequences to identify signatures and functional correlates of tumor-specific CD4+ T cells infiltrating human melanoma. Conventional CD4+ T cells that recognize tumor neoantigens express CXCL13 and are subdivided into clusters expressing memory ...[more]

PMID: 35413271

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Project description:BackgroundCellular immunotherapies using autologous tumor-infiltrating lymphocytes (TIL) can induce durable regression of epithelial cancers in selected patients with treatment-refractory metastatic disease. As the genetic engineering of T cells with tumor-reactive T-cell receptors (TCRs) comes to the forefront of clinical investigation, the rapid, scalable, and cost-effective detection of patient-specific neoantigen-reactive TIL remains a top priority.MethodsWe analyzed the single-cell transcriptomic states of 31 neoantigen-specific T-cell clonotypes to identify cell surface dysfunction markers that best identified the metastatic transcriptional states enriched with antitumor TIL. We developed an efficient method to capture neoantigen-reactive TCRs directly from resected human tumors based on cell surface co-expression of CD39, programmed cell death protein-1, and TIGIT dysfunction markers (CD8+ TILTP).ResultsTILTP TCR isolation achieved a high degree of correlation with single-cell transcriptomic signatures that identify neoantigen-reactive TCRs, making it a cost-effective strategy using widely available resources. Reconstruction of additional TILTP TCRs from tumors identified known and novel antitumor TCRs, showing that at least 39.5% of TILTP TCRs are neoantigen-reactive or tumor-reactive. Despite their substantial enrichment for neoantigen-reactive TCR clonotypes, clonal dynamics of 24 unique antitumor TILTP clonotypes from four patients indicated that most in vitro expanded TILTP populations failed to demonstrate neoantigen reactivity, either by loss of neoantigen-reactive clones during TIL expansion, or through functional impairment during cognate neoantigen recognition.ConclusionsWhile direct usage of in vitro-expanded CD8+ TILTP as a source for cellular therapy might be precluded by profound TIL dysfunction, isolating TILTP represents a streamlined effective approach to rapidly identify neoantigen-reactive TCRs to design engineered cellular immunotherapies against cancer.

Dataset Information

Neoantigen-specific CD4⁺ T cells in human melanoma have diverse differentiation states and correlate with CD8⁺ T cell, macrophage, and B cell function.

Publications

Neoantigen-specific CD4<sup>+</sup> T cells in human melanoma have diverse differentiation states and correlate with CD8<sup>+</sup> T cell, macrophage, and B cell function.

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