Autophagy Regulation of Metabolism Is Required for CD8+ T Cell Anti-tumor Immunity

DeVorkin, Lindsay; Pavey, Nils; Carleton, Gillian; Comber, Alexandra P.; Ho, Cally J; Lim, Junghyun; McNamara, Erin; Huang, Haochu; Kim, Paul; Zacharias, Lauren G.; Mizushima, Noboru; Saitoh, Tatsuya; Akira, Shizuo; Beckham, Wayne; Lorzadeh, Alireza; Moksa, Michelle; Cao, Qi; Murthy, Aditya; Hirst, Martin; DeBerardinis, Ralph J.; Lum, Julian J.

doi:10.1016/j.celrep.2019.03.037

Cited by 139 publications

(129 citation statements)

References 55 publications

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“…Certain subsets of suppressor immune cells may be more or less susceptible to autophagy inhibition. produced striking rejection of tumor implants in syngeneic mouse tumor models (100). Work by Mgrditchian and colleagues has shown that genetic inhibition of BECN1 augments infiltration of T cells into the immune microenvironment (101).…”

Section: Autophagy and Tumor Immunitymentioning

confidence: 99%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

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Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specifi c autophagy inhibitors for cancer treatment, and review future directions for autophagy research. Signifi cance: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor microenvironment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefi t from this approach.

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Section: Autophagy and Tumor Immunitymentioning

confidence: 99%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

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“…175,176 Autophagy also supports T cell function in anti-tumor immunity. 177 In addition, autophagy is upregulated in Treg cells compared to naïve CD4 + T cells, and it promotes Treg cell responses for suppression of autoimmunity, anti-tumor immunity and other inflammatory disorders. 26,178 These effects are attributed, in part, to reduced Treg cell survival in the absence of autophagy.…”

Section: Autophagymentioning

confidence: 99%

“…26 Heightened glycolysis has also been observed in autophagy-deficient CD8 + T cells. 177 Thus, autophagy supports many aspects of T cell fitness and function.…”

Section: Autophagymentioning

confidence: 99%

Signaling networks in immunometabolism

Saravia¹,

Raynor²,

Chapman³

et al. 2020

Cell Res

156

136

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Adaptive immunity is essential for pathogen and tumor eradication, but may also trigger uncontrolled or pathological inflammation. T cell receptor, co-stimulatory and cytokine signals coordinately dictate specific signaling networks that trigger the activation and functional programming of T cells. In addition, cellular metabolism promotes T cell responses and is dynamically regulated through the interplay of serine/threonine kinases, immunological cues and nutrient signaling networks. In this review, we summarize the upstream regulators and signaling effectors of key serine/threonine kinase-mediated signaling networks, including PI3K-AGC kinases, mTOR and LKB1-AMPK pathways that regulate metabolism, especially in T cells. We also provide our perspectives about the pending questions and clinical applicability of immunometabolic signaling. Understanding the regulators and effectors of immunometabolic signaling networks may uncover therapeutic targets to modulate metabolic programming and T cell responses in human disease.

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“…Importantly, CD8 + T cell memory generation and maintenance require of autophagy activity [138]. Recent works indicate that the ability of autophagy to reprogram CD8 + T cell metabolism, contributes in modulation of the efficacy of anti-tumor CD8 + T cell responses [139,140] (Figure 2).…”

Section: Macroautophagy In the Adaptive Immune Responsementioning

confidence: 99%

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

Molina

García‐Bernal

Valdor

2019

Cancers

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Glioblastoma (GB) has been shown to up-regulate autophagy with anti- or pro-oncogenic effects. Recently, our group has shown how GB cells aberrantly up-regulate chaperone-mediated autophagy (CMA) in pericytes of peritumoral areas to modulate their immune function through cell-cell interaction and in the tumor’s own benefit. Thus, to understand GB progression, the effect that GB cells could have on autophagy of immune cells that surround the tumor needs to be deeply explored. In this review, we summarize all the latest evidence of several molecular and cellular immunosuppressive mechanisms in the perivascular tumor microenvironment. This immunosuppression has been reported to facilitate GB progression and may be differently modulated by several types of autophagy as a critical point to be considered for therapeutic interventions.

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Autophagy Regulation of Metabolism Is Required for CD8+ T Cell Anti-tumor Immunity

Abstract: Highlights d Inactivation of T cell autophagy results in enhanced tumor rejection d T cells deficient in autophagy show increased glucose uptake and lactate production d Reduction in SAM transcriptionally reprograms immune cells toward effector memory

Cited by 139 publications

References 55 publications

Targeting Autophagy in Cancer: Recent Advances and Future Directions

Targeting Autophagy in Cancer: Recent Advances and Future Directions

Signaling networks in immunometabolism

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

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