Zhang et al. profiled PD-1+CD8+ T cells from patients with advanced melanoma who received anti-PD-1+anti-CTLA-4 or only anti-PD-1 therapy. Dual ICB more effectively modified the exhaustion profile to boost a cytotoxic effector program and expand melanoma-reactive clonotypes, and drove a STAT usage pattern linked to IL-21 signaling. Dual ICB also induced IL-21 production by CD4+ TFH cells. In an anti-CTLA-4 monotherapy clinical trial, induction of IL-21 signaling in patients’ CD8+ T cells was observed. CTLA-4 blockade was ineffective in mouse melanoma models employing anti-IL-21R blockade, and in hosts with IL-21R-deficient CD8+ T cells.
Contributed by Paula Hochman
ABSTRACT: The mechanisms underlying the efficacy of anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) therapy are incompletely understood. Here, by immune profiling responding PD-1(+)CD8(+) T (T(Resp)) cell populations from patients with advanced melanoma, we identified differential programming of T(Resp) cells in response to combination therapy, from an exhausted toward a more cytotoxic effector program. This effect does not occur with anti-PD-1 monotherapy. Single-cell transcriptome and T cell receptor repertoire analysis was used to identify altered effector programming of expanding PD-1(+)CD8(+) T cell clones with distinct regulon usage, STAT1 and STAT3 utilization and antitumor specificity connected to interleukin (IL)-21 signaling in combination and anti-CTLA-4 monotherapy. Therapeutic efficacy of CTLA-4 blockade was lost in B16F10 melanoma models with either Il21r(-) deficiency or anti-IL-21 receptor blockade. Together, these results show how IL-21 signaling to T(Resp) is critical for anti-CTLA-4-based checkpoint therapies and highlight major signaling differences to anti-PD-1 monotherapy.
Author Info: (1) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany.
Author Info: (1) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (2) Faculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany. (3) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (4) Faculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany. (5) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (6) Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. (7) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (8) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (9) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (10) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (11) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (12) Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. (13) Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. (14) Department of Dermatology and Venereology, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany. (15) Department of Dermatology and Venereology, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany. (16) Department of Dermatology and Venereology, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany. (17) Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany. (18) Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany. (19) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (20) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. Department of Gastroenterology and Hepatology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany. (21) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (22) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (23) Institute of Medical Bioinformatics and Systems Medicine, University Medical Center Freiburg, Freiburg, Germany. (24) Department of Dermatology and Venereology, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany. (25) Faculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany. (26) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. (27) Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. (28) Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany. bertram.bengsch@uniklinik-freiburg.de. Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. bertram.bengsch@uniklinik-freiburg.de. German Cancer Consortium (DKTK) Heidelberg, Germany, Partner Site Freiburg, Freiburg, Germany. bertram.bengsch@uniklinik-freiburg.de.
