Virassamy et al. demonstrated the presence of two phenotypically and transcriptionally distinct CD8+ T cell sub-populations in syngeneic murine TNBC: terminally exhausted CD69+CD103- T cells (TEX) and tissue-resident memory-like CD69+CD103+ T cells (TRM) that transcriptionally resembled TRM cells from healthy murine tissues and human TNBC. Dual-ICB therapy resulted in TCR-Vβ clonal expansion and diversification, increased cytokine production and cytotoxicity of TRM cells in TNBC tumors, and local immune protection against tumor rechallenge by these TRM cells. The CD8+ TRM cell gene signature from tumor-free mice after dual-ICB was associated with better response to ICB in TNBC patients.
Contributed by Shishir Pant
ABSTRACT: CD8(+) tumor-infiltrating lymphocytes with a tissue-resident memory T (T(RM)) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8(+) T(RM) cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8(+) T cells in murine mammary tumors transcriptionally resemble those from TNBC patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (T(EX)-like) and the other with a bona fide resident phenotype (T(RM)-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in expansion of these intratumoral populations, with the T(RM)-like subset displaying significantly enhanced cytotoxic capacity. T(RM)-like CD8(+) T cells could also provide local immune protection against tumor rechallenge and a T(RM) gene signature extracted from tumor-free tissue was significantly associated with improved clinical outcomes in TNBC patients treated with checkpoint inhibitors.
Author Info: (1) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (2) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Author Info: (1) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (2) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (3) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia. (4) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia. (5) Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia. (6) Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. (7) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (8) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (9) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (10) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia. (11) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (12) Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. (13) Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. (14) German Breast Cancer Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany. (15) German Breast Cancer Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany; Department of Pathology, University Marburg-Giessen, Campus Marburg, Germany. (16) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (17) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia. (18) German Breast Cancer Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany; Department of Pathology, University Marburg-Giessen, Campus Marburg, Germany. (19) German Breast Cancer Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany. (20) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Computational Cancer Genomics Research Group, University College London Cancer Institute, London, UK. (21) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (22) Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC, Australia. (23) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia. Electronic address: phil.darcy@petermac.org. (24) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia. Electronic address: paul.neeson@petermac.org. (25) Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. Electronic address: lkmackay@unimelb.edu.au. (26) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia. Electronic address: sherene.loi@petermac.org.
