Humblin et al. showed that sustained ICOS signaling impaired CD8+ T cell survival and function during chronic antigen exposure. ICOS was expressed on the surface of TCF-1+ Tpex cells, and genetic ablation of ICOS led to enrichment of FoxO1 target genes and memory-like features of Tpex cells. ICOS deficiency promoted virus-specific effector-like Tex cell differentiation, survival, and functionality in chronic LCMV infection in a FoxO1-dependent manner. ICOSL blockade expanded virus- and tumor-specific effector-like PD-1+CD8+ T cells, reduced viral load and tumor growth, and potentiated PD-1 targeted immunotherapy.
Contributed by Shishir Pant
ABSTRACT: During persistent antigen stimulation, CD8(+) T cell responses are maintained by progenitor exhausted CD8(+) T (Tpex) cells. Tpex cells respond to blockade of the inhibitory receptor programmed cell death-1 (PD-1), and regulation of their differentiation is critical for immunotherapies. Tpex cells highly express inducible costimulator (ICOS), but how ICOS modulates PD-1(+)CD8(+) T cells is not clear. During chronic infection, intrinsic ICOS deficiency increased number and quality of virus-specific CD8(+) T cells. Loss of ICOS potentiated activity of the transcription factor forkhead box O1 (FoxO1) and memory-like features of Tpex cells. ICOS-deficient Tpex cells were poised to generate effecor-like cells with improved survival and cytokine production. ICOS-ligand (ICOSL) blockade expanded effector-like PD-1(+)CD8(+) T cells, reduced viral load, and improved response to PD-1 blockade. Similarly, in a mouse model of hepatocellular carcinoma, ICOS inhibition enhanced tumor-specific CD8(+) T cell responses and tumor control by PD-1 blockade. Overall, we show that sustained ICOS costimulation limits CD8(+) T cell responses during chronic antigen exposure.
Author Info: (1) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS
Author Info: (1) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. Electronic address: etienne.humblin@gmail.com. (2) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. (3) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. (4) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. (5) Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Department of Oncological Sciences, ISMMS, New York, NY 10029, USA. (6) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (7) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. (8) Federal University of Alagoas, Arapiraca Campus, Center of Medical Sciences, Bom Sucesso, Alagoas 57309, Brazil. (9) Department of Microbiology, ISMMS, New York, NY 10029, USA. (10) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Genomics Institute, ISMMS, New York, NY 10029, USA. (11) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. (12) Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of So Paulo, So Paulo 05508, Brazil; Hospital Israelita Albert Einstein, So Paulo 05620, Brazil. (13) Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Department of Oncological Sciences, ISMMS, New York, NY 10029, USA. (14) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA; Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Icahn Genomics Institute, ISMMS, New York, NY 10029, USA. (15) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Department of Oncological Sciences, ISMMS, New York, NY 10029, USA. (16) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Department of Oncological Sciences, ISMMS, New York, NY 10029, USA; Department of Pathology, ISMMS, New York, NY 10029, USA. (17) Department of Microbiology, ISMMS, New York, NY 10029, USA. (18) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA; Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Department of Oncological Sciences, ISMMS, New York, NY 10029, USA. Electronic address: alice.kamphorst@mssm.edu.
