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Single cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy

ABSTRACT: We report the application of single cell RNA and TCR sequencing technology on 22 bone marrow aspirates from 8 AML patients. By exploring 60753 AML cells and 52641 tumor microenvironment cells, we show that TCR repertoires expand and primarily emerge from CD8+ cells in responsive patients, but contract in therapy-resistant patients.Tractory analysis reveals that CD8 + T cells in AML are on continuum with GZMK expression being enriched in a memory subset of CD8 + T cells. Also, Chromosome 7/7q loss s an intrinsic AML biomarker of resistance to ICB-therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198052 | GEO | 2022/03/10

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 T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy

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