Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy

Shannon N Geels; Alexander Moshensky; Rachel S Sousa; Claire Murat; Matias A Bustos; Benjamin L Walker; Rima Singh; Stacey N Harbour; Giselle Gutierrez; Michael Hwang; Thorsten R Mempel; Casey T Weaver; Qing Nie; Dave S B Hoon; Anand K Ganesan; Shivashankar Othy; Francesco Marangoni

doi:10.1016/j.ccell.2024.05.013

Interruption of the intratumor CD8⁺ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy

Cancer Cell. 2024 Jun 10;42(6):1051-1066.e7. doi: 10.1016/j.ccell.2024.05.013.

Authors

Shannon N Geels¹, Alexander Moshensky¹, Rachel S Sousa², Claire Murat¹, Matias A Bustos³, Benjamin L Walker⁴, Rima Singh⁵, Stacey N Harbour⁶, Giselle Gutierrez⁷, Michael Hwang¹, Thorsten R Mempel⁸, Casey T Weaver⁶, Qing Nie⁹, Dave S B Hoon³, Anand K Ganesan¹⁰, Shivashankar Othy¹, Francesco Marangoni¹¹

Affiliations

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; 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.
³ Department of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, CA, USA.
⁴ 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.
⁵ Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
⁶ Department of Pathology, University of Alabama, Birmingham, Birmingham, AL, USA.
⁷ Institute for Immunology, University of California, Irvine, Irvine, CA, USA.
⁸ Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁹ 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.
¹⁰ Department of Dermatology, University of California, Irvine, Irvine, CA, USA.
¹¹ 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.

PMID: 38861924
PMCID: PMC11285091 (available on 2025-06-10)
DOI: 10.1016/j.ccell.2024.05.013

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.

Keywords: CD8(+) T cells; F-IVM; ICOS; IL-2; PD-1; T regulatory cells; Treg; functional intravital microscopy; melanoma; tumor tolerance.

MeSH terms

Animals
CD8-Positive T-Lymphocytes* / immunology
Cell Line, Tumor
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Immunotherapy* / methods
Inducible T-Cell Co-Stimulator Protein* / metabolism
Interleukin-2* / immunology
Melanoma* / drug therapy
Melanoma* / immunology
Melanoma* / therapy
Melanoma, Experimental / immunology
Melanoma, Experimental / therapy
Mice
Mice, Inbred C57BL
Programmed Cell Death 1 Receptor* / antagonists & inhibitors
Programmed Cell Death 1 Receptor* / immunology
Programmed Cell Death 1 Receptor* / metabolism
Signal Transduction
T-Lymphocytes, Regulatory* / immunology

Substances

Programmed Cell Death 1 Receptor
Inducible T-Cell Co-Stimulator Protein
Immune Checkpoint Inhibitors
Interleukin-2
PDCD1 protein, human
ICOS protein, human

Abstract

MeSH terms

Substances

Grants and funding