{
  "abstract": "Background The combination of antiangiogenic therapy with immune checkpoint blockade has demonstrated significant clinical benefits in various cancers, however, the precise mechanisms of action on the immune system are not fully understood. In particular, the early intratumoral immune responses induced by angiogenesis inhibition remain unclear.Methods Using preclinical models of colorectal cancer, we examined the immune changes elicited by combined vascular endothelial growth factor receptor-2 (VEGFR-2) and programmed cell death protein-1 (PD-1) blockade.Results Our findings reveal that CD8 T cells respond directly and early to VEGFR-2 inhibition, preceding the acquisition of overt cytotoxic function. Shortly after treatment, intratumoral CD8 T cells expanded and produced interleukin-10 (IL-10). Unexpectedly, this CD8 T cell-derived IL-10 promoted the recruitment of natural killer (NK) cells into tumors. Recruited NK cells subsequently gained effector activity and produced granulocyte-macrophage colony-stimulating factor, which supported macrophage maturation and the induction of CXCL11. This sequence of events enhanced secondary CD8 T-cell infiltration and sustained antitumor immune activity. Disruption of IL-10 signaling or NK-cell function eliminated the therapeutic benefit of combined VEGFR-2 and PD-1 blockade, whereas regulatory T-cell depletion further improved tumor control.Conclusions Together, these findings identify an unanticipated role for CD8 T cell-derived IL-10 in coordinating early innate and adaptive immune responses following angiogenesis inhibition and define an immune program initiated by VEGFR-2 blockade that is required for therapeutic efficacy in two preclinical colorectal cancer models.",
  "authors": [
    {
      "affiliations": [
        "Université Bourgogne Europe, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Mannon Geindreau"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Cassandre Pignol"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Loïs Coënon"
    },
    {
      "affiliations": [
        "Université de Franche-Comté, UBFC, EFS, Inserm UMR RIGHT, Besançon, France"
      ],
      "name": "Alexis Varin"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, UMR INSERM 1231, TIRECs team, Dijon, France",
        "Immunology and Immunotherapy of Cancer Laboratory, EPHE, PSL Research University, Paris, Île-de-France, France"
      ],
      "name": "Cindy Racoeur"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Lylou Milian"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Nolwenn Roger"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Cancer Biology 14 Transfer Platform, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Fanny Chalmin"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Cancer Biology 14 Transfer Platform, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Thibault Vernet"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Line Alibert"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, UMR INSERM 1231, TIRECs team, Dijon, France",
        "Centre Georges-François Leclerc, Service de médecine nucléaire, Plateforme d'imagerie et de 16 radiothérapie précliniques, Dijon, Bourgogne-Franche-Comté, France"
      ],
      "name": "Pierre-Simon Bellaye"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Cancer Biology 14 Transfer Platform, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Marion Thibaudin"
    },
    {
      "affiliations": [
        "Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia"
      ],
      "name": "Cynthia Louis"
    },
    {
      "affiliations": [
        "Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia"
      ],
      "name": "Ian Wicks"
    },
    {
      "affiliations": [
        "Université de Franche-Comté, UBFC, EFS, Inserm UMR RIGHT, Besançon, France"
      ],
      "name": "Caroline Truntzer"
    },
    {
      "affiliations": [
        "Unité de Biologie Moléculaire, Georges-François Leclerc Centre, Dijon, Bourgogne-Franche-Comté, France"
      ],
      "name": "Romain Boidot"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, UMR INSERM 1231, TIRECs team, Dijon, France",
        "Immunology and Immunotherapy of Cancer Laboratory, EPHE, PSL Research University, Paris, Île-de-France, France"
      ],
      "name": "Catherine Paul"
    },
    {
      "affiliations": [
        "Université de Franche-Comté, UBFC, EFS, Inserm UMR RIGHT, Besançon, France"
      ],
      "name": "Baptiste Lamarthée"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Cancer Biology 14 Transfer Platform, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Frederique Vegran"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Cancer Biology 14 Transfer Platform, UMR INSERM 1231, TIRECs team, Dijon, France",
        "Genetic and Immunology Medical Institute, Dijon, Bourgogne-Franche-Comté, France",
        "Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France"
      ],
      "name": "Francois Ghiringhelli"
    },
    {
      "affiliations": [
        "Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Cancer Biology 14 Transfer Platform, UMR INSERM 1231, TIRECs team, Dijon, France"
      ],
      "name": "Mélanie Bruchard"
    }
  ],
  "title": "IL-10 secretion by CD8 T cells orchestrates early NK cell recruitment and antitumor immunity after anti-VEGFR-2/PD-1 therapy",
  "uid": "2f6b5d93-21be-53c1-9077-c363e72e3420"
}