Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response

Poillet-Perez, Laura; Sharp, Daniel W.; Yang, Yang; Laddha, Saurabh V.; Ibrahim, Maria; Bommareddy, Praveen K.; Hu, Zhixian; Vieth, Joshua A.; Haas, Michael; Bosenberg, Marcus W.; Rabinowitz, Joshua D.; Cao, Jian; Guan, Jun; Ganesan, Shridar; Chan, Chang S.; Mehnert, Janice M.; Lattime, Edmund C.; White, Eileen

doi:10.1038/s43018-020-00110-7

Cited by 80 publications

(79 citation statements)

References 48 publications

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“…Cells with inactivated autophagy upregulate the production and secretion of proinflammatory cytokines [e.g., type I and II IFNs, and tumor necrosis factor-α (TNFα)]. Mice with essential autophagy genes deleted display induction of proinflammatory cytokines [e.g., type I and II IFNs, TNFα, chemokine (C-C motif) ligand 2 (CCL2), and C-X-C motif chemokine ligand 10 (CXCL10)] [8,35]. It is likely that some of the damage induced in normal tissues in autophagydeficient mice is due to unchecked innate immune activation, and this may also underlie human diseases associated with compromised function of essential autophagy genes, such as Crohn's disease, which is a risk factor for colon cancer.…”

Section: Autophagy-mediated Immune Evasionmentioning

confidence: 99%

“…In vivo experiments demonstrated that autophagy suppresses the ability of T cells to kill tumor cells, and this correlates with lower type II IFNγ expression [42]. Conversely, inactivation of autophagy in mice promotes the recognition and rejection of a variety of antigenic tumors by T cells [35,43]. Thus, autophagy is an important inhibitor of the innate and adaptive immune responses that creates a permissive environment for tumor immune evasion and growth.…”

Section: Autophagy Suppresses Tumor Killing By T Cellsmentioning

confidence: 99%

“…Hepatic Autophagy Immune Tolerance Autophagy-deficient host mice have T cells that are more efficient at rejecting antigenic tumors compared with autophagy-proficient mice [35]. In stark contrast to tumors grown on autophagy-proficient hosts, those grown on autophagy-deficient hosts show enhanced immune infiltration and gene expression signatures of activated type I and II IFN pathways.…”

Section: Inhibition Of Antigen Presentation By Autophagymentioning

confidence: 99%

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Autophagy Regulates Stress Responses, Metabolism, and Anticancer Immunity

2021

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Section: Autophagy-mediated Immune Evasionmentioning

confidence: 99%

Section: Autophagy Suppresses Tumor Killing By T Cellsmentioning

confidence: 99%

Section: Inhibition Of Antigen Presentation By Autophagymentioning

confidence: 99%

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Autophagy Regulates Stress Responses, Metabolism, and Anticancer Immunity

2021

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“…In host cells, autophagy can support tumor growth by providing essential nutrients in circulation or within the TME [66][67][68]. In addition to supplying nutrients, host autophagy counteracts key immunosurveillance mechanisms within the TME [69]. The functional role of autophagy in the tumor-associated vasculature, especially in response to stressful conditions like hypoxia and uncontrolled angiogenesis in the TME, remains an open question.…”

Section: Heightened Autophagy Is a Hallmark Of The Tmementioning

confidence: 99%

Endothelial cell autophagy in homeostasis and cancer

et al. 2021

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Autophagy, the major lysosomal pathway for the degradation and recycling of cytoplasmic materials, is increasingly recognized as a major player in endothelial cell (EC) biology and vascular pathology. Particularly in solid tumors, tumor microenvironmental stress such as hypoxia, nutrient deprivation, inflammatory mediators, and metabolic aberrations stimulates autophagy in tumor‐associated blood vessels. Increased autophagy in ECs may serve as a mechanism to alleviate stress and restrict exacerbated inflammatory responses. However, increased autophagy in tumor‐associated ECs can re‐model metabolic pathways and affect the trafficking and surface availability of key mediators and regulators of the interplay between EC and immune cells. In line with this, heightened EC autophagy is involved in pathological angiogenesis, inflammatory, and immune responses. Here, we review major cellular and molecular mechanisms regulated by autophagy in ECs under physiological conditions and discuss recent evidence implicating EC autophagy in tumor angiogenesis and immunosurveillance.

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“…Intriguingly, defective autophagy in Tregs or in adult mice dramatically enhances anti-tumor immunity via loss of Tregs or generation of a potent effector memory T cell pool in pre-clinical models ( Xu et al, 2014 ; DeVorkin et al, 2019 ). Recent studies have highlighted the need for sophisticated genetic models to delineate the role of autophagy in lymphocyte developmental versus function in adult tissues ( DeVorkin et al, 2019 ; Laura Poillet-Perez, 2020 ). DeVorkin et al demonstrated that inducible deletion of Atg5 in adult mice enhanced T cell glycolytic metabolism while maintaining oxidative phosphorylation (OXPHOS).…”

Section: Tumor-extrinsic Autophagymentioning

confidence: 99%

Targeting Autophagy to Treat Cancer: Challenges and Opportunities

Lim¹,

Murthy²

2020

Front. Pharmacol.

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Autophagy is a catabolic process that targets its cargo for lysosomal degradation. In addition to its function in maintaining tissue homeostasis, autophagy is recognized to play a context-dependent role in cancer. Autophagy may inhibit tumor initiation under specific contexts; however, a growing body of evidence supports a pro-tumorigenic role of this pathway in established disease. In this setting, autophagy drives treatment resistance, metabolic changes, and immunosuppression both in a tumor-intrinsic and extrinsic manner. This observation has prompted renewed interest in targeting autophagy for cancer therapy. Novel genetic models have proven especially insightful, revealing unique and overlapping roles of individual autophagy-related genes in tumor progression. Despite identification of pharmacologically actionable nodes in the pathway, fundamental challenges still exist for successful therapeutic inhibition of autophagy. Here we summarize the current understanding of autophagy as a driver of resistance against targeted and immuno-therapies and highlight knowledge gaps that, if addressed, may provide meaningful advances in the treatment of cancer.

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Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response

Cited by 80 publications

References 48 publications

Autophagy Regulates Stress Responses, Metabolism, and Anticancer Immunity

Autophagy Regulates Stress Responses, Metabolism, and Anticancer Immunity

Endothelial cell autophagy in homeostasis and cancer

Targeting Autophagy to Treat Cancer: Challenges and Opportunities

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