In addition to these unbiased analyses of tumor resistance, we will focus on one resistance pathway of particular interest: Expression of PD-L1 has emerged as the key immune inhibitory pathway in human cancers, but our understanding of PD-L1 protein regulation is highly limited. Through comparative genomic and immunological analysis of pre- and post-therapy tumors we will determine the clinical importance of tumor cell-intrinsic mechanisms of acquired resistance, and will identify novel mechanisms of such resistance.ģ). We will complement this analysis of baseline tumor sensitivity with a systematic analysis of acquired immunotherapy resistance in patients treated with T cell checkpoint blockade. We will address this fundamental question by analysis of the sensitivity of human tumors to defined T cell effector mechanisms, and subsequent correlation to patient outcome upon immunotherapeutic intervention.Ģ). While we know that T cell activity in human tumors can lead to cancer regression, we do not know whether such regression is mostly mediated by T cell secreted cytokines or granzyme mediated lysis. In this effort, I will focus on 3 linked questions:ġ). Summary The goal of this project is to describe the tumor cell-intrinsic mechanisms that determine whether ‘foreign’ human cancers are sensitive or resistant to the tumor-specific T cell response they induce. (-) Remove United Kingdom (311) filter United Kingdom (311).(-) Remove Turkey (5) filter Turkey (5).(-) Remove Switzerland (85) filter Switzerland (85).(-) Remove Sweden (50) filter Sweden (50).(-) Remove Spain (62) filter Spain (62).(-) Remove Slovenia (3) filter Slovenia (3).(-) Remove Serbia (1) filter Serbia (1).(-) Remove Romania (6) filter Romania (6).
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