![]() ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating TFAM, which led to mitochondrial DNA leakage into the cytoplasm. Furthermore, chemical inhibition of ATM significantly potentiated anti-PD1 therapy of mouse tumors. Genetic depletion of ATM in murine cancer cells significantly delayed tumor growth in syngeneic mouse hosts in a T-cell dependent manner. ![]() Here we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA and activation of the cGAS/STING pathway. However, the molecular mechanism involved is not clearly elucidated. Recent data indicated that ATM might be a promising target to enhance immune checkpoint blockade (ICB) therapy. Ataxia Telangiectasia Mutated (ATM) protein plays a central role in sensing DNA double strand breaks and coordinating their repair. Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Therefore, tumor-selective targeting of glutamine metabolism may be a promising therapeutic strategy in TNBC. We propose a “glutamine steal” scenario, in which cancer cells deprive tumor-infiltrating lymphocytes of needed glutamine, thus impairing anti-tumor immune responses. The glutamine transporter inhibitor V-9302 selectively blocked glutamine uptake by TNBC cells but not CD8+ T cells, driving synthesis of GSH, a major cellular antioxidant, to improve CD8+ T cell effector function. We found that tumor cell-specific loss of glutaminase (GLS), a key enzyme for glutamine metabolism, improved anti-tumor T cell activation in both a spontaneous mouse TNBC model and orthotopic grafts. Here, we report that there is an inverse correlation between glutamine metabolic genes and markers of T cell-mediated cytotoxicity in human basal-like breast cancer (BLBC) patient datasets, with increased glutamine metabolism and decreased T cell cytotoxicity associated with poor survival. The amino acid glutamine is consumed by effector T cells and glutamine-addicted triple-negative breast cancer (TNBC) cells, suggesting that a metabolic competition for glutamine may exist within the tumor microenvironment, potentially serving as a therapeutic intervention strategy. Rapidly proliferating tumor and immune cells need metabolic programs that support energy and biomass production. These abundant anticancer neoepitopes, which have not been tested in human studies thus far, can be exploited for the generation of personalized human cancer vaccines. ![]() T cells elicited by the active neoepitopes identified here demonstrated a stem-like early dysfunctional phenotype associated with effective responses against viruses and tumors of transgenic mice. Structural modeling showed how the MHC I-presented neoepitopes have an altered conformation, higher stability, or increased exposure to T cell receptors as compared to the un-mutated counterparts. These results from a single mouse model were validated in another, antigenically distinct mouse cancer model, and are consistent with data reported in human studies. It also revealed that our current methods of prediction discard the overwhelming majority of true anticancer neoepitopes. This analysis uncovered a large trove of effective anticancer neoepitopes which have strikingly different properties from conventional epitopes and suggested an algorithm to predict them. ![]() Here, using an entirely unbiased approach, we queried all possible neoepitopes in a mouse cancer model and asked which of those are effective in mediating tumor rejection, and independently, in eliciting a measurable CD8 response. Identification of neoepitopes that are effective in cancer therapy is a major challenge in creating cancer vaccines.
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