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Single-cell RNA and TCR sequencing reveals distinct systematic immune response induced by SABR with or without prior anti-PD-1 therapy

ABSTRACT: Previous studies have demonstrated that stereotactic body radiation therapy (SBRT) could activate systemic immune response, however, these researches showed limitations in comprehensively characterizing changes of T cell profile and T cell receptor (TCR). In the present study, we applied scRNA-seq and scTCR-seq to observe the dynamics of T cell and TCR repertoire from peripheral blood mononuclear cells (PBMCs) in early stage non-small-cell lung cancer (NSCLC) patients receiving SBRT with or without prior anti-PD-1 therapy, demonstrating the distinct systemic immune response between SBRT and ISBRT group. An enrichment of CD8-TE, CD8-EM, and CD4-TE clusters with increased cytotoxic and exhausted score were observed after treatment in SBRT group, while a decrease of those were presented in ISBRT group. Moreover, gene expression analysis revealed T cell mediated cytotoxicity signaling and T cell proliferation signaling were enriched in SBRT group while decreased in SBRT group. Analysis of TCR repertoire indicated a substantial alteration of TCR repertoire after treatment. The proportions of the large clone of TCR were increased after treatment in SBRT group while an opposite alteration existed in ISBRT group. After treatment, both SBRT and ISBRT group generated numerous new TCR clones which were mainly enriched in CD8 TE. Single clones and large clones were the mainly types of new TCRs in SBRT group, whereas in ISBRT group single clones accounted for the majority of new TCRs. These findings suggested that systemic immunity was activated in distinct pattern between the SBRT and ISBRT group, and provide evidence for future development of new treatment regimen.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190905 | GEO | 2025/02/05

REPOSITORIES: GEO

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Project description:Background Clinical success of T cell receptor (TCR) gene therapy has previously been demonstrated for NY-ESO-1 TCR gene therapy. To increase numbers of cancer patients that can be treated with TCR gene therapy we aimed to identify a novel set of high-affinity cancer specific TCRs targeting different cancer testis (CT) antigens in prevalent HLA class I alleles. Methods In this study, we selected based on publicly available gene expression databases the most promising CT genes to target. From these selected genes we identified by HLA peptidomics the naturally processed and presented HLA class I peptides. With these peptide-HLA tetramers were generated, and by single cell sorting CT specific CD8+ T cells were selected, and expanded from the allo-HLA repertoire of healthy donors. By several functional assays high avidity CT-specific T cell clones with safe recognition pattern were selected. To evaluate the potential for clinical application in TCR gene therapy, TCRs were sequenced and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 in the context of human leukocyte antigen(HLA) -A1, -A2, -A3, -B7, -B35 and -C7. TCR gene transfer into CD8⁺ T cells resulted in efficient cytokine production and cytotoxicity of variety of different tumor types without detectable cross-reactivity. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells was observed in an orthotopic xenograft model for established multiple myeloma, in which bone marrow located tumor cells were completely eradicated after T cell injection. Conclusion The identification of 7 novel CT-specific TCRs, reactive against CT antigens presented in a variety of different HLA class I alleles, allows selection of therapeutic TCRs for an increased number of cancer patients, and will improve development of personalized TCR gene therapy.

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Single-cell RNA and TCR sequencing reveals distinct systematic immune response induced by SABR with or without prior anti-PD-1 therapy

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