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.