Escobar et al. showed that tumor immunogenicity determines the reliance of tumor antigen-specific CD8+ T cells on TCF1 expression for ICB response. TCF1 was dispensable for T cell priming and therapy response in highly immunogenic tumors, but was essential for optimal priming of CD8+ T cells and ICB response in poorly immunogenic tumors that accumulate TOX+ dysfunctional T cells. Loss of TCF1 destabilized the dysfunctional intratumoral CD8+ T cells that shared features with CD8+ T cells in ICB non-responder patients. In poorly immunogenic tumors, therapeutic vaccination or increase in antigen presentation overcame TCF1 dependency for ICB response.
Contributed by Shishir Pant
ABSTRACT: Stem-like CD8(+) T cells are regulated by T cell factor 1 (TCF1) and are considered requisite for immune checkpoint blockade (ICB) response. However, recent findings indicate that reliance on TCF1(+)CD8(+) T cells for ICB efficacy may differ across tumor contexts. We find that TCF1 is essential for optimal priming of tumor antigen-specific CD8(+) T cells and ICB response in poorly immunogenic tumors that accumulate TOX(+) dysfunctional T cells, but is dispensable for T cell priming and therapy response in highly immunogenic tumors that efficiently expand transitory effectors. Importantly, improving T cell priming by vaccination or by enhancing antigen presentation on tumors rescues the defective responses of TCF1-deficient CD8(+) T cells upon ICB in poorly immunogenic tumors. Our study highlights TCF1's role during the early stages of anti-tumor CD8(+) T cell responses with important implications for guiding optimal therapeutic interventions in cancers with low TCF1(+)CD8(+) T cells and low-neo-antigen expression.
Author Info: (1) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (2) Evergrande
Author Info: (1) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (2) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. (3) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (4) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (5) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (6) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (7) Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA. (8) Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA. (9) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (10) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (11) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (12) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (13) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (14) Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; US Department of Veterans Affairs, VA Maryland Health Care System, Baltimore, MD 21201, USA. (15) Great Ormond Street Institute of Child Health, University College London, London, UK. (16) Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Electronic address: acanderson@bwh.harvard.edu.
