Geels et al. studied the impact of PD-1 blockade on immunosuppressive Tregs in murine models of melanoma and patients with metastatic melanoma. PD-1 blockade resulted in increased Treg accumulation in tumors, which colocalized with activated CD8+ T cells. CD8+ T cells produced IL-2, which stimulated anti-apoptosis ICOS production by Tregs, promoting Treg expansion. ICOS inhibition prior to (but not concurrent with) PD-1 blockade decreased tumor Tregs, preserved CD8+ T cells levels, and improved tumor growth control compared with PD-1 monotherapy, suggesting the translational potential of interrupting CD8+ T cell:Treg crosstalk.
Contributed by Katherine Turner
ABSTRACT: PD-1 blockade unleashes potent antitumor activity in CD8(+) T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8(+) T cells. CD8(+) T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8(+) T cell:Treg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.
Author Info: (1) Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. (2) Ins
Author Info: (1) Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. (2) Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. (3) Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA. (4) Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. (5) Department of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, CA, USA. (6) Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA. (7) Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA. (8) Department of Pathology, University of Alabama, Birmingham, Birmingham, AL, USA. (9) Institute for Immunology, University of California, Irvine, Irvine, CA, USA. (10) Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. (11) Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (12) Department of Pathology, University of Alabama, Birmingham, Birmingham, AL, USA. (13) Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA. (14) Department of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, CA, USA. (15) Department of Dermatology, University of California, Irvine, Irvine, CA, USA. (16) Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. (17) Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. Electronic address: f.marangoni@uci.edu.
