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Exhausted TILs are a subset of tumor antigen enriched T cells in solid tumors that often have diminished ability to response to standard immunotherapies and to combat tumor growth. Exhausted TILs can likely be revitalized in multiple ways to allow this important T cell subset to control tumor growth in patients. We have found that the endoplasmic reticulum (ER) stress response is a central component of T cell exhaustion and we have demonstrated that targeting ER stress can revitalize T cell response to immunotherapy, leading to tumor regression. We use conditional knock out mouse models, human tumor samples, spectral flow cytometry, and RNA-seq to understand which components of the ER stress response are important to target to enhance immunotherapeutic efficacy.
Metabolic programs define differential T cell lineages. In solid tumors the metabolic program of tumor infiltrating lymphocytes (TILs) is often incompatible with persistence in the harsh tumor microenvironment and infusion of exogenous TILs or CAR T cells often results in a similar fate. A strategy to improve multiple types of immunotherapies is to use metabolic remodeling to rewire the fate of immune cells toward antitumor traits that allow persistence in vivo as well as robust effector function needed to eliminate established solid tumors. This type of therapy can improve cellular and checkpoint-based therapies, inducing complete responses in mouse models. We aim to partner with industry and clinicians to move our findings into clinical trials. We use techniques such as metabolomics, carbon tracing, RNA-seq, and Seahorse Bioanalysis to study metabolic programming in tumor immunity.
Mitochondrial morphology has been shown to define TIL antitumor efficacy and unique therapeutics that restore mitochondrial dynamics can augment multiple immunotherapies. We are studying the role that the ER plays in tuning mitochondrial dynamics as well as the appropriate morphological state that the ER of T cells must display for immunotherapies to be effective. Moreover, we are monitoring ER dynamics in all immune susbets, both pro and anti-tumorigenic, to understand how ER morphology shapes intratumoral immunity. This work will lead to development of multiple highly unique ER-based immunotherapeutic targets.
Human immunotherapy predictors of response
From clinical trials that we have been a part of in collaboration with our clinical partners, we have acquired tumor tissue from cancer patients that responded or showed no response to checkpoint therapies. Using nanoString GeoMx Digital Spatial Profiling, we have obtained large data sets that will allow us to understand the metabolic state of T cells in trial patient tumors correlated with response status. These studies will enrich our understanding of T cell metabolic efficacy in tumors.