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      Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti- PD-1 therapy

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          Summary

          Despite compelling rates of durable clinical responses to PD-1 blockade, advances are needed to extend these benefits to resistant tumors. We found that tumor-bearing mice deficient in the chemokine receptor CXCR3 responded poorly to anti-PD-1 treatment. CXCR3 and its ligand CXCL9 were critical for a productive CD8 + T cell response in tumor-bearing mice treated with anti-PD-1, but were not required for the infiltration of CD8 + T cells into tumors. The anti-PD-1- induced anti-tumor response was facilitated by CXCL9 production from intratumoral CD103 + dendritic cells, suggesting that CXCR3 facilitates dendritic cell-T cell interactions within the tumor microenvironment. CXCR3 ligands within murine tumors and in plasma of melanoma patients were an indicator of clinical response to anti-PD-1, and their induction in non- responsive murine tumors promoted responsiveness to anti-PD-1. Our data suggest that the CXCR3 chemokine system is a biomarker for sensitivity to PD-1 blockade and that augmenting the intratumoral function of this chemokine system could improve clinical outcomes.

          eTOC Blurb

          Chow et al. find the CXCR3 chemokine system is not required for CD8 + T cell migration into the tumor, but rather for the enhancement of the intratumoral CD8 + T cell response in the context of PD-1 blockade. The CXCR3 chemokine system may serve as a biomarker for sensitivity to PD- 1 blockade and a target for improving clinical outcomes.

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          Author and article information

          Journal
          9432918
          8591
          Immunity
          Immunity
          Immunity
          1074-7613
          1097-4180
          1 May 2019
          13 May 2019
          18 June 2019
          18 June 2020
          : 50
          : 6
          : 1498-1512.e5
          Affiliations
          [1 ]Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
          [2 ]Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
          [3 ]Cutaneous Biology Research Center, Department of Dermatology and MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
          [4 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
          [5 ]Lead contact
          Author notes

          Author Contributions

          Conceptualization, M.T.C. and A.D.L.; Investigation, M.T.C., A.J.O., R.L.S. and A.D.L.; Resources, D.T.F., J.A.L., D.E.F., G.J.F., G.M.B.; Writing, M.T.C. and A.D.L.; Funding Acquisition, M.T.C. and A.D.L.; Supervision, A.D.L.

          [* ]Correspondence: aluster@ 123456mgh.harvard.edu
          Article
          PMC6527362 PMC6527362 6527362 nihpa1528323
          10.1016/j.immuni.2019.04.010
          6527362
          31097342
          7173d302-9a85-4eb8-8a92-c01e919e6f93
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