Transcriptomic profiles of neoantigen-reactive T cells in human gastrointestinal cancers
Chunhong Zheng, Joseph N Fass, Yi-Ping Shih, Andrew J Gunderson, Nelson Sanjuan Silva, Huayu Huang, Brady M Bernard, Venkatesh Rajamanickam, Joseph Slagel, Carlo B Bifulco, Brian Piening, Pippa H A Newell, Paul D Hansen, Eric Tran, Chunhong Zheng, Joseph N Fass, Yi-Ping Shih, Andrew J Gunderson, Nelson Sanjuan Silva, Huayu Huang, Brady M Bernard, Venkatesh Rajamanickam, Joseph Slagel, Carlo B Bifulco, Brian Piening, Pippa H A Newell, Paul D Hansen, Eric Tran
Abstract
Tumor-infiltrating neoantigen-reactive T cells can mediate regression of metastatic gastrointestinal cancers yet remain poorly characterized. We performed immunological screening against personalized neoantigens in combination with single-cell RNA sequencing on tumor-infiltrating lymphocytes from bile duct and pancreatic cancer patients to characterize the transcriptomic landscape of neoantigen-reactive T cells. We found that most neoantigen-reactive CD8+ T cells displayed an exhausted state with significant CXCL13 and GZMA co-expression compared with non-neoantigen-reactive bystander cells. Most neoantigen-reactive CD4+ T cells from a patient with bile duct cancer also exhibited an exhausted phenotype but with overexpression of HOPX or ADGRG1 while lacking IL7R expression. Thus, neoantigen-reactive T cells infiltrating gastrointestinal cancers harbor distinct transcriptomic signatures, which may provide new opportunities for harnessing these cells for therapy.
Keywords: adoptive cell therapy; bile duct cancer; cancer immunotherapy; gastrointestinal cancers; neoantigen; pancreatic cancer; single-cell RNA-seq; tumor-infiltrating lymphocytes.
Conflict of interest statement
Declaration of interests E.T. is on the scientific advisory board of PACT Pharma, Genocea Biosciences, and Turnstone Biologics. C.B.B. reports a consultant/advisory relationship with BMS, has stock ownership in and is on the scientific board of PrimeVax, and is on the scientific board of BioAI and LunaPhore. Other authors declare no competing interests.
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Source: PubMed