@article{fe9e8e6db3e34a839fae6d204f31f4d7,
title = "Transcriptomic profiles of neoantigen-reactive T cells in human gastrointestinal cancers",
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",
author = "Chunhong Zheng and Fass, {Joseph N.} and Shih, {Yi Ping} and Gunderson, {Andrew J.} and {Sanjuan Silva}, Nelson and Huayu Huang and Bernard, {Brady M.} and Venkatesh Rajamanickam and Joseph Slagel and Bifulco, {Carlo B.} and Brian Piening and Newell, {Pippa H.A.} and Hansen, {Paul D.} and Eric Tran",
note = "Funding Information: We are grateful to the Providence Portland Medical Foundation (PPMF) and donors to the PPMF for funding this study. Part of this study was supported by the Cholangiocarcinoma Foundation Jacques Dupont Memorial Research Fellowship awarded to C.Z. This research was also supported by a Sidney Kimmel Foundation Scholar award to E.T. We thank the patients involved in this study and members of Providence Health and Services and the EACRI who were involved with patient care and sample acquisition. We thank Jared J. Gartner for assistance in setting up the neoantigen bioinformatics pipeline. We also thank Dr. Walter J. Urba for careful reading of the manuscript, and Dr. Giacomo Oliveira and Dr. Catherine J. Wu for providing single cell RNA-seq data from their study. Funding Information: We are grateful to the Providence Portland Medical Foundation (PPMF) and donors to the PPMF for funding this study. Part of this study was supported by the Cholangiocarcinoma Foundation Jacques Dupont Memorial Research Fellowship awarded to C.Z. This research was also supported by a Sidney Kimmel Foundation Scholar award to E.T. We thank the patients involved in this study and members of Providence Health and Services and the EACRI who were involved with patient care and sample acquisition. We thank Jared J. Gartner for assistance in setting up the neoantigen bioinformatics pipeline. We also thank Dr. Walter J. Urba for careful reading of the manuscript, and Dr. Giacomo Oliveira and Dr. Catherine J. Wu for providing single cell RNA-seq data from their study. C.Z. and E.T. conceived the experiments; C.Z. Y.S. N.S.S. and H.H. performed the experiments; A.J.G. performed multiplex immunofluorescence staining and laser capture microdissection; C.Z. J.N.F. and E.T. analyzed the single-cell sequencing data; J.N.F. B.M.B. V.R. J.S. C.B.B. B.P. and E.T. were involved in the acquisition and/or analysis of the neoantigen bioinformatics data; P.D.H. and P.H.N. collected clinical samples; C.Z. and E.T. wrote the manuscript. 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. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = apr,
day = "11",
doi = "10.1016/j.ccell.2022.03.005",
language = "English",
volume = "40",
pages = "410--423.e7",
journal = "Cancer Cell",
issn = "1535-6108",
number = "4",
}