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      CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation

      , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
      Cancer Discovery
      American Association for Cancer Research (AACR)

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          Abstract

          <p class="first" id="P2">Immune checkpoint blockade, exemplified by antibodies targeting the programmed death-1 (PD-1) receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T cell activation, contributing to anti-tumor effects <i>in vivo</i>, due in part to de-repression of Nuclear Factor of Activated T cell (NFAT) family proteins and their target genes, critical regulators of T cell function. Although CDK4/6 inhibitors decrease T cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel <i>ex vivo</i> organotypic tumor spheroid culture system and in multiple <i>in vivo</i> murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies. </p>

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          Author and article information

          Journal
          Cancer Discovery
          Cancer Discov
          American Association for Cancer Research (AACR)
          2159-8274
          2159-8290
          February 04 2018
          February 03 2018
          : 8
          : 2
          : 216-233
          Article
          10.1158/2159-8290.CD-17-0915
          5809273
          29101163
          de1d2017-0280-46d1-b384-1c1f6b39bcc6
          © 2018
          History

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