Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy.

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From: Cell(Vol. 185, Issue 16)
Publisher: Elsevier B.V.
Document Type: Report
Length: 484 words

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Keywords T cells; cancer; immunotherapy; neoadjuvant therapy; tissue-resident memory T cells; single-cell RNA sequencing Highlights * Neoadjuvant ICB induces local and systemic T cell responses in oral cancer patients * Treatment-responsive T cell clones recognize self-antigens including tumor antigens * Responding T cells in tumors display a tissue-resident memory program * Circulating PD-1+KLRG1-CD8 T cell frequency correlates with pathological response Summary Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity. Author Affiliation: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA (2) Department of Immunology, Harvard Medical School, Boston, MA 02115, USA (3) Guangzhou Laboratory, Guangzhou, Guangdong 510005, China (4) TScan Therapeutics, Waltham, MA 02451, USA (5) Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, MA 02115, USA (6) Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA (7) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA (9) Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA (10) Howard Hughes Medical Institute and Koch Institute of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA (11) Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA * Corresponding author Article History: Received 27 November 2021; Revised 26 April 2022; Accepted 9 June 2022 (miscellaneous) Published: July 7, 2022 (footnote)12 Present address: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA (footnote)13 These authors contributed equally (footnote)14 Senior author (footnote)15 Lead contact Byline: Adrienne M. Luoma (1,2,13), Shengbao Suo [suo_shengbao@gzlab.ac.cn] (1,2,3,13,*), Yifan Wang (4), Lauren Gunasti (5), Caroline B.M. Porter (6), Nancy Nabilsi (4), Jenny Tadros (4), Andrew P. Ferretti (4), Sida Liao (4), Cagan Gurer (4), Yu-Hui Chen (7), Shana Criscitiello (5), Cora A. Ricker (8), Danielle Dionne (6), Orit Rozenblatt-Rosen (6), Ravindra Uppaluri (8,9), Robert I. Haddad (8), Orr Ashenberg (6), Aviv Regev (6,10,12), Eliezer M. Van Allen (8), Gavin MacBeath (4), Jonathan D. Schoenfeld [jonathan_schoenfeld@dfci.harvard.edu] (5,14,**), Kai W. Wucherpfennig [kai_wucherpfennig@dfci.harvard.edu] (1,2,11,14,15,***)

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Gale Document Number: GALE|A712585156