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Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. By profiling 47 cell lines with pharmacological and genetic loss-of-function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of autophagy-related 7 (ATG7) by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy.

The clinical success of immune checkpoint inhibitors that target cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1) demonstrates that reactivation of the human immune system delivers durable responses for some patients and represents an exciting approach for cancer treatment. The combination of multiple immunotherapies as well as the combination of immunotherapy with targeted therapy is being pursued vigorously to increase the rate and extend the duration of response. Preclinical in vivo models for immuno-oncology (IO) typically require immunocompetent mice bearing murine syngeneic tumors. To facilitate translation of preclinical studies into human, we characterized the genomic, transcriptomic, and protein expression of a panel of mouse tumor cell lines grown in vitro culture as well as in vivo tumor samples. Our studies identified many genetic and cellular phenotypic differences that distinguish murine syngeneic models from human cancers. For example, only a small fraction of the somatic single nucleotide variants (SNVs) in mouse cell lines directly match SNVs from human actionable cancer genes. At the cellular level, some epithelial tumor models have a more mesenchymal phenotype with relatively low T-lymphocyte infiltration compared to the corresponding human cancers. Furthermore, in contrast to what has been reported for human tumors, we did not observe a correlation between neoantigen load and cytolytic activity in syngeneic models. Finally, the relative immunogenicity of syngeneic tumors does not typically resemble that of human tumors of the same tissue origin. CT26, a colon tumor model, had the highest immunogenicity and was the most responsive model to CTLA4 inhibitor treatment, by contrast to the relatively low immunogenicity and response rate to checkpoint inhibitor therapies in human colon cancers. These differences highlight limitations of syngeneic models for evaluating novel immune therapies and rationalize some of the challenges associated with translating preclinical findings to clinical studies.