Selective depletion of virus-specific CD8 T cells from the liver after PD-1 therapy with Fc-intact antibody during chronic infection
(1) Hashimoto M (2) Nasti TH (3) Jin HT (4) Bu M (5) Araki K (6) Lee J (7) Valanparambil RM (8) Akhtar A (9) Khan MA (10) Peng Z (11) Hu Y (12) McManus DT (13) Bahhar I (14) Wieland A (15) Davis CW (16) Ramalingam SS (17) Sharpe AH (18) Ravetch JV (19) Freeman GJ (20) Ahmed R
Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth.
Contributed by Ute Burkhardt
(1) Hashimoto M (2) Nasti TH (3) Jin HT (4) Bu M (5) Araki K (6) Lee J (7) Valanparambil RM (8) Akhtar A (9) Khan MA (10) Peng Z (11) Hu Y (12) McManus DT (13) Bahhar I (14) Wieland A (15) Davis CW (16) Ramalingam SS (17) Sharpe AH (18) Ravetch JV (19) Freeman GJ (20) Ahmed R
Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth.
Contributed by Ute Burkhardt
ABSTRACT: Anti-programmed cell death 1 (PD-1) antibody therapy is now widely used in various cancers. However, the role of the antibody Fc region in PD-1 directed immunotherapy is not well understood. Preclinical studies commonly use species-mismatched rat anti-mouse antibodies, which may not accurately reflect antibody-Fc gamma receptor (Fc_R) interactions. Here, we used mouse anti-mouse PD-1 antibodies to investigate how the Fc region influences therapeutic efficacy for enhancing CD8 T cell responses using mouse models of chronic lymphocytic choriomeningitis virus infection and CT26 tumors. Treatment with these mouse anti-mouse PD-1 antibodies caused preferential depletion of PD-1+ virus-specific CD8 T cells in the liver, resulting in increased viral titers. These effects of mouse anti-PD-1 antibodies were Fc dependent since mutating the Fc region to block Fc_R interaction prevented PD-1+ CD8 T cell depletion and resulted in effective immunotherapy. Using mice lacking activating Fc_R III or inhibitory Fc_R IIb, we found that depletion of PD-1+ CD8 T cells was mediated via activating Fc_R III. Furthermore, we determined that phagocytic cells, not natural killer cells, were the in vivo effectors that mediated depletion of PD-1+ CD8 T cells. Similar depletion of tumor-specific CD8 T cells and reduced tumor control were observed in the CT26 model with Fc-intact mouse anti-mouse PD-1 treatment. These findings highlight potential negative effects of Fc-functional anti-PD-1 antibodies in therapies for liver cancer, liver metastases, and chronic hepatotropic viral infections. Conversely, Fc_R-mediated depletion could benefit "agonistic" anti-PD-1 antibodies for treatment of autoimmunity. Our research emphasizes the importance of Fc region in tailoring PD-1 therapies for diverse clinical applications.
Author Info:
(1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
(2) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (3) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. CHA Biotech, CHA Bio Complex, Seongnam-si, Gyeonggi-do 13488, Republic of Korea. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. Medical Scientist Training Program, UCSF Graduate Division, School of Medicine, University of California, San Francisco, CA 94143. (5) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229. (6) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Viral Immunology Laboratory, Institut Pasteur Korea, Seongnam 13488, Republic of Korea. (7) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (8) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (9) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar 140001, India. (10) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (11) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (12) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (13) Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210. (14) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210. (15) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (16) Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322. (17) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA (18) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. (20) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322.
Citation: Proc Natl Acad Sci U S A 2026 Apr 14 123:e2427192123 Epub04/08/2026
