Hanada et al. performed CITEseq with TCRseq on tumor-infiltrating lymphocytes from fresh non-small cell lung cancer tumors, and developed a signature of neoantigen-reactive T cells that enabled the rapid identification of neoantigen-reactive TCRs on both CD4+ and CD8+ T cells. High-frequency TCR clonotype, CD39 protein expression, and high CXCL13 mRNA co-expression identified neoantigen-reactive TCRs with a success rate of 45% for CD8+ and 66% for CD4+ T cells, and led to the identification of additional HLA class-I- and class-II-restricted neoantigen-reactive TCRs.
Contributed by Shishir Pant
ABSTRACT: A common theme across multiple successful immunotherapies for cancer is the recognition of tumor-specific mutations (neoantigens) by T cells. The rapid discovery of such antigen responses could lead to improved therapies through the adoptive transfer of T cells engineered to express neoantigen-reactive T cell receptors (TCRs). Here, through CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) and TCR-seq of non-small cell lung cancer (NSCLC) tumor-infiltrating lymphocytes (TILs), we develop a neoantigen-reactive T cell signature based on clonotype frequency and CD39 protein and CXCL13 mRNA expression. Screening of TCRs selected by the signature allows us to identify neoantigen-reactive TCRs with a success rate of 45% for CD8(+) and 66% for CD4(+) T cells. Because of the small number of samples analyzed (4 patients), generalizability remains to be tested. However, this approach can enable the quick identification of neoantigen-reactive TCRs and expedite the engineering of personalized neoantigen-reactive T cells for therapy.
Author Info: (1) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: hanada@nih.gov. (2) Surgery B
Author Info: (1) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: hanada@nih.gov. (2) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (3) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (4) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (5) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (6) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (7) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (8) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (9) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (10) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (11) CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21701, USA. (12) Single Cell Analysis Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Bethesda, MD 20892, USA. (13) Single Cell Analysis Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Bethesda, MD 20892, USA. (14) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (15) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (16) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (17) Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jamesyang@mail.nih.gov.
