Hanna and Llaó-Cid et al. identified subsets of CD8+ T cells with either intermediate or high PD-1 expression in CLL patients and a mouse model. PD-1int cells expressed TCF-1 and were functionally competent, whereas PD-1hi cells represented a functionally impaired exhausted T cell population. Genetic and pharmacological inhibition of IL-10R–STAT3 signaling led to accumulation of PD-1hi CD8+ T cells, altered chromatin and reduced AP-1 DNA accessibility, impaired CD8+ T cell proliferation, and accelerated CLL progression in vivo. In patients with cancer, loss of IL-10R–STAT3 signaling correlated with CD8+ T cell exhaustion and poor survival.
Contributed by Shishir Pant
ABSTRACT: T cell exhaustion limits anti-tumor immunity and responses to immunotherapy. Here, we explored the microenvironmental signals regulating T cell exhaustion using a model of chronic lymphocytic leukemia (CLL). Single-cell analyses identified a subset of PD-1(hi), functionally impaired CD8(+) T cells that accumulated in secondary lymphoid organs during disease progression and a functionally competent PD-1(int) subset. Frequencies of PD-1(int) TCF-1(+) CD8(+) T cells decreased upon Il10rb or Stat3 deletion, leading to accumulation of PD-1(hi) cells and accelerated tumor progression. Mechanistically, inhibition of IL-10R signaling altered chromatin accessibility and disrupted cooperativity between the transcription factors NFAT and AP-1, promoting a distinct NFAT-associated program. Low IL10 expression or loss of IL-10R-STAT3 signaling correlated with increased frequencies of exhausted CD8(+) T cells and poor survival in CLL and in breast cancer patients. Thus, balance between PD-1(hi), exhausted CD8(+) T cells and functional PD-1(int) TCF-1(+) CD8(+) T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.
Author Info: (1) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: bola.hanna@hms.harvard.edu. (2) Molecular Genetics, German Cancer Resea
Author Info: (1) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: bola.hanna@hms.harvard.edu. (2) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany. (3) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (4) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (5) Chromatin Networks, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (6) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (7) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (8) School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK. (9) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (10) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (11) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (12) Institut d'Investigacions Biomdiques August Pi i Sunyer (IDIBAPS), Hematopathology Unit, Pathology Department, Hospital Clinic, CIBERONC, University of Barcelona, 08036 Barcelona, Spain. (13) Institut d'Investigacions Biomdiques August Pi i Sunyer (IDIBAPS), Hematopathology Unit, Pathology Department, Hospital Clinic, CIBERONC, University of Barcelona, 08036 Barcelona, Spain. (14) Internal Medicine III, University of Ulm, 89081 Ulm, Germany. (15) Internal Medicine III, University of Ulm, 89081 Ulm, Germany. (16) Medicine V, University Hospital Heidelberg, 69120 Heidelberg, Germany. (17) Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany. (18) Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany. (19) Chromatin Networks, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (20) Immune Tolerance, Tumor Immunology Program, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Chair for Immunology, Regensburg Center for Interventional Immunology (RCI), University of Regensburg, 93053 Regensburg, Germany. (21) School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK. (22) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (23) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (24) Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: m.seiffert@dkfz.de.
