Exploring the mechanism of resistance to PD-1 axis blockade in advanced bladder cancer, Salomé et al. identified a novel NKG2A+ population of CD8+ T cells with innate-like TCR-independent tumor targeting capabilities. NKG2A+ cells differentiated from exhausted T cells along an alternative pathway, expressed high levels of activating receptor DNAM-1, and acquired resident memory features. Tumor cell expression of HLA-E (an inhibitory ligand for NKG2A) abrogated activity and high KLRC1 (gene for NKG2A) expression correlated with better survival in the IMVIGOR210 trial, supporting the combination of anti-NKG2A (blocking the interaction with HLA-E) and anti-PD-1 axis therapy.
Contributed by Ed Fritsch
ABSTRACT: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8(+) T cells. In bladder tumors, NKG2A is acquired on CD8(+) T cells later than PD-1 as well as other well-established immune checkpoints. NKG2A(+) PD-1(+) CD8(+) T cells diverge from classically defined exhausted T cells through their ability to react to human leukocyte antigen (HLA) class I-deficient tumors using T cell receptor (TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder tumors is progressively diminished as disease progresses, framing the importance of targeting TCR-independent anti-tumor functions. Notably, NKG2A(+) CD8(+) T cells are inhibited when HLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a framework for subsequent clinical trials combining NKG2A blockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E.
Author Info: (1) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Can
Author Info: (1) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (2) Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (3) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (4) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (5) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (6) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (7) Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA; Department of Human Genetics, Genentech, South San Francisco, CA 94080, USA. (8) Department of Oncology Biomarker Development, Genentech, South San Francisco, CA 94080, USA. (9) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (10) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (11) Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (12) Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (13) Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (14) Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (15) Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (16) Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (17) Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (18) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (19) Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (20) Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (21) Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (22) Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. (23) Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. (24) Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Sema4, a Mount Sinai Venture, Stamford, CT 06902, USA. (25) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (26) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (27) Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (28) Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (29) Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (30) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (31) Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Sema4, a Mount Sinai Venture, Stamford, CT 06902, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (32) AstraZeneca, Oncology R & D Unit, Gaithersburg, MD 20878, USA. (33) AstraZeneca, Oncology R & D Unit, Gaithersburg, MD 20878, USA. (34) AstraZeneca, Oncology R & D Unit, Gaithersburg, MD 20878, USA. (35) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (36) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (37) Department of Experimental Medicine, University of Genoa, Genoa, Italy. (38) Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. (39) Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (40) Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA. (41) Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA. (42) Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA. (43) Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. (44) Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (45) Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (46) Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA. (47) Department of Oncology Biomarker Development, Genentech, South San Francisco, CA 94080, USA. (48) Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Sema4, a Mount Sinai Venture, Stamford, CT 06902, USA. (49) Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (50) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: nina.bhardwaj@mssm.edu. (51) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: amir.horowitz@mssm.edu.
