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Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy.
Geels, Shannon N; Moshensky, Alexander; Sousa, Rachel S; Murat, Claire; Bustos, Matias A; Walker, Benjamin L; Singh, Rima; Harbour, Stacey N; Gutierrez, Giselle; Hwang, Michael; Mempel, Thorsten R; Weaver, Casey T; Nie, Qing; Hoon, Dave S B; Ganesan, Anand K; Othy, Shivashankar; Marangoni, Francesco.
Afiliación
  • Geels SN; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
  • Moshensky A; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
  • Sousa RS; 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.
  • Murat C; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
  • Bustos MA; Department of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, CA, USA.
  • Walker BL; 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.
  • Singh R; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
  • Harbour SN; Department of Pathology, University of Alabama, Birmingham, Birmingham, AL, USA.
  • Gutierrez G; Institute for Immunology, University of California, Irvine, Irvine, CA, USA.
  • Hwang M; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
  • Mempel TR; Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Weaver CT; Department of Pathology, University of Alabama, Birmingham, Birmingham, AL, USA.
  • Nie Q; 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.
  • Hoon DSB; Department of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, CA, USA.
  • Ganesan AK; Department of Dermatology, University of California, Irvine, Irvine, CA, USA.
  • Othy S; Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
  • Marangoni F; 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.
Cancer Cell ; 42(6): 1051-1066.e7, 2024 Jun 10.
Article en En | MEDLINE | ID: mdl-38861924
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 cellTreg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interleucina-2 / Linfocitos T Reguladores / Linfocitos T CD8-positivos / Proteína Coestimuladora de Linfocitos T Inducibles / Receptor de Muerte Celular Programada 1 / Inhibidores de Puntos de Control Inmunológico / Inmunoterapia / Melanoma Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interleucina-2 / Linfocitos T Reguladores / Linfocitos T CD8-positivos / Proteína Coestimuladora de Linfocitos T Inducibles / Receptor de Muerte Celular Programada 1 / Inhibidores de Puntos de Control Inmunológico / Inmunoterapia / Melanoma Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos