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      Loss of PTEN associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma

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          Summary

          Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers may inform immunotherapy mediators. We identified a treatment-naïve patient with metastatic uterine leiomyosarcoma who experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed primary tumor, the sole treatment-resistant metastasis, and germline tissue to explore mechanisms of immunotherapy sensitivity and resistance. Both tumors stained diffusely for PD-L2, with sparse PD-L1 staining. PD-1 + cell infiltration significantly decreased in the resistant tumor (p=0.02). Genomically, the treatment-resistant tumor uniquely harbored biallelic PTEN loss and had reduced expression of two neoantigens that demonstrated strong immunoreactivity with patient T cells in vitro, suggesting long-lasting immunological memory. In this near-complete response to PD-1 blockade in a mesenchymal tumor, we identified PTEN mutation and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.

          eTOC Blurb

          George et al. report an exceptional responder to anti-PD-1 monotherapy in uterine leiomyosarcoma and propose mediators of treatment sensitivity and resistance. Neoantigen-directed immunoreactivity was associated with sensitivity to anti-PD-1 monotherapy, whereas resistance was associated with reduction in neoantigen expression consistent with immune evasion, and biallelic PTEN loss associated with induction of an immunosuppressive microenvironment.

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          Author and article information

          Journal
          9432918
          8591
          Immunity
          Immunity
          Immunity
          1074-7613
          1097-4180
          17 March 2017
          21 February 2017
          21 February 2018
          : 46
          : 2
          : 197-204
          Affiliations
          [1 ]Department of Medical Oncology; Dana-Farber Cancer Institute; Boston, MA 02215; USA
          [3 ]Broad Institute of MIT and Harvard; Cambridge, MA 02142; USA
          [4 ]Department of Pathology; Brigham and Women’s Hospital; Boston, MA 02215; USA
          [5 ]Center for Immuno-Oncology; Dana-Farber Cancer Institute; Boston, MA 02215; USA
          [6 ]Department of Surgery; Brigham and Women’s Hospital; Boston, MA 02215; USA
          [7 ]Center for Cancer Precision Medicine; Dana-Farber Cancer Institute; Boston, MA 02215; USA
          Author notes
          Correspondence: Eliezer M. Van Allen, M.D. eliezerm_vanallen@ 123456dfci.harvard.edu
          [2]

          Co-first author

          [8]

          Lead contact

          Article
          PMC5408320 PMC5408320 5408320 nihpa857774
          10.1016/j.immuni.2017.02.001
          5408320
          28228279
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