Project 3: Modeling and overcoming resistance to melanoma immunotherapy

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PROJECT 3 ABSTRACT We have started to make progress in defining mechanisms that lead to primary and acquired resistance to anti- PD-1/L1 therapy at the molecular level. In this Project, we propose to characterize their biology, discover how to overcome resistance based on mechanistic understanding, and study how this knowledge can improve patient care. In Aim 1, we will develop in vitro and in vivo models to study the biology of molecularly-defined resistance mechanisms with the goal of providing full mechanistic understanding of how they mediate resistance. This is based on our discovery of homozygous loss of function (LoF) mutations in the interferon (IFN) receptor pathway and in the antigen presenting machinery (APM) in biopsies of patients with primary and acquired resistance to PD-1 blockade therapy, both confirmed with data from other groups. With this information, we will be in the position to test combination approaches to overcome resistance to anti-PD-1/L1 therapy. These include approaches aimed at inducing a local IFN response that may activate this pathway downstream, such as toll-like receptor (TLR) or MDA5 agonists in JAK1/2 knockout models, and activating natural killer (NK) cells in B2M knockout models. In Aim 2, we will study a new cancer cell-intrinsic mechanisms of T cell exclusion mediated by the expression of the p21 associated kinase 4 (PAK4), which we have recently uncovered by comparing gene expression in T cell-rich versus T cell-poor biopsies of patients with melanoma on therapy with anti-PD-1. We will examine the mechanisms leading to T cell exclusion induced by PAK4 in mouse models, and we will analyze the mechanisms in biopsies obtained from patients enrolled in a clinical trial combining the PAK4 inhibitor KPT-9274 and the anti-PD-1 antibody nivolumab. Sample analyses for the two aims will benefit from the collaboration with investigators from the other two projects and cores of this P01. In conclusion, this Project will analyze defined mechanisms of therapeutic resistance to cancer immunotherapy to provide improved understanding on their effects, and show how to overcome the resistance using rationally designed combination studies. 1