Rebalancing protein homeostasis enhances tumor antigen presentation

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PROJECT SUMMARY / ABSTRACT Cancers arise through a combination of genetic and epigenetic changes that facilitate their immortality, but simultaneously create foreign antigens, which should render neoplastic cells detectable by the immune system and target them for destruction. Despite the remarkable success of immunotherapies targeting endogenous effector T-cells, many cancers still evade immune recognition. A critical component of successful immunotherapy is robust antigen presentation through Major Histocompatibility Complex Class I (MHC-I) [10, 15, 34]. Since antigens can be derived from the mutant proteome present in cancers, it would be expected that tumor types with high mutational load, such as lung adenocarcinoma (LUAD), are characterized by strong T cell responses. However, many patients with these tumor types either fail to respond to immunotherapy, or relapse after initial treatment. Inherent to malignant transformation is the induction of proteotoxic stress due to the accumulation of mutated, conformationally aberrant proteins [5]. To overcome these stresses, cancer cells are exquisitely dependent on molecular chaperones [28]. This phenomenon suggests that immunogenicity generated by antigens derived from the aberrant genome and epigenome in cancer is dampened by the function of chaperones and the protein folding machinery. Thus, I hypothesize that inducers of protein misfolding stress lead to increased antigen presentation by MHC-I molecules and increased immunogenicity. I propose to explore the impact of destabilizing the mutant proteome of LUAD in order to reveal it to the host’s immune system. The aims are as follows: Aim 1: Analyze the impact of protein misfolding stress on antigen presentation by MHC-I molecules. In this aim I will interrogate the impact of subtoxic doses of small molecule modulators of protein folding on antigen presentation in human and murine LUAD cell lines. We expect to expose the mutant proteome to the immune system without disrupting protein folding machineries essential functions. Additionally, I will genetically and pharmacologically perturb the pathways involved in antigen presentation, in order to understand the mechanisms by which modulators of proteotoxic stress amplify and diversify antigen presentation in LUAD cell lines. Aim 2: Analyze the role of HSP90i and other inducers of proteotoxic stress in a hyper-mutational mouse model of lung adenocarcinoma (LUAD) Low-dose treatment with modulators of cytoplasmic proteotoxic stress will be tested for their ability to stimulate an anti-tumor response in a hyper-mutational mouse model of LUAD. This proposal will highlight mechanistically novel strategies to drive anti-tumor immune responses.