Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

Galluzzi, Lorenzo; Pedro, José Manuel Bravo-San; Levine, Beth; Green, Douglas R.; Kroemer, Guido

doi:10.1038/nrd.2017.22

Cited by 658 publications

(566 citation statements)

References 305 publications

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“…Apparently such partial autophagy defects do not cause a major immunosuppressive effect, supporting the idea that autophagy in the tumor cells (rather than autophagy in immune effectors) is relevant to the therapeutic outcome of immunogenic chemotherapy. 36,37 …”

Section: Resultsmentioning

confidence: 99%

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

et al. 2018

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The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate. Tumor growth reduction by MTX treatment is known to depend on autophagy induction in cancer cells as well as on an intact immune system. We compared the antitumor effects of MTX on autophagy-competent cancers implanted in wild type (WT) or partially autophagy-deficient (Becn1± or Atg4b−/-) mice. While there was no difference in the tumor growth reducing effects of MTX on tumors evolving in WT, Becn1+/- and Atg4b−/- mice, we observed an increase in the toxicity of MTX on Atg4b−/- mice. These results suggest that autophagy in cancer cells (but less so in host cells) is rate-limiting for therapeutically relevant anticancer immune responses, yet has a major role in blunting the life-threatening toxicity of chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

et al. 2018

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“…279,280 In multiple clinical studies, bona fide ICD-inducing chemotherapeutic regimens are combined with agents that elicit ICD per se, such as radiation therapy (2 trials), or considerably boost the immunogenicity of cancer cells, such as taxanes or zoledronic acid (10 trials). Finally, in a limited amount of trials, ICD inducers are combined with targeted anticancer agents, including the inhibitor of JAK kinases ruxolitinib (1 trial) and the inhibitor of mechanistic target of rapamycin kinase (MTOR) rapamycin 281,282 (also known as sirolimus, or its derivative everolimus) (2 trials) ( Tables 1 and 2).…”

Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

et al. 2017

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The expression "immunogenic cell death" (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as "damage-associated molecular patterns". Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.

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“…In co‐culture experiments, A549, HCT 116, and HepG2 cells treated with 8 Gy plus decitabine elicited a secretory and proliferative T‐cell response that could be blocked with monoclonal antibodies specific for CD40, CD80, or MHC Class I molecules . Mouse melanoma B16F10 cells, mouse lung carcinoma LLC cells, and mouse breast carcinoma 4T1 cells responded to a single RT dose of 20 Gy in vitro by exposing mannose‐6‐phosphate receptor, cation dependent (M6PR) on their membrane upon autophagy activation . In this setting, M6PR was required for B16F10 melanoma cells growing in immunocompetent, syngeneic C57BL/6 mice to optimally respond to three RT doses of 15 Gy each given in combination with a cytotoxic T lymphocyte associated protein 4 (CTLA4)‐targeting monoclonal antibody .…”

Section: On‐target Immunological Effectsmentioning

confidence: 99%

“…Indeed, the elevated amounts of energy that RT deposits onto malignant cells cause considerable damage to macromolecules, in particular DNA and lipids . Not surprisingly, irradiated cancer cells activate a panel of adaptive stress responses that attempt to repair damage and restore cellular homeostasis, including (but presumably not limited to) the DNA damage response, the unfolded protein response, and autophagy . When damage is excessive, these responses fail and malignant cells undergo either of two terminal fates: (i) they enter an irreversible proliferative arrest that is associated with specific biochemical processes including the release of bioactive molecules (ie, cellular senescence); or (ii) they commit suicide upon the activation of one or multiple signal transduction cascades with lethal consequences (ie, they undergo regulated cell death, RCD) .…”

Section: Introductionmentioning

confidence: 99%

Immune recognition of irradiated cancer cells

Wennerberg

Vanpouille-Box

Bornstein

et al. 2017

Immunological Reviews

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Summary Ionizing irradiation has been extensively employed for the clinical management of solid tumors, with therapeutic or palliative intents, for decades. Until recently, radiation therapy (RT) was believed to mediate antineoplastic activity mostly (if not only) as a consequence of cancer cell-intrinsic effects. Indeed, the macromolecular damage imposed to malignant cells by RT initiates one or multiple signal transduction cascades that drive a permanent proliferative arrest (cellular senescence) or regulated cell death. Both these phenomena show a rather linear dose-response correlation. However, RT also mediates consistent immunological activity, not only as an “on-target effect” originating within irradiated cancer cells, but also as an “off-target effect” depending on the interaction between RT and stromal, endothelial and immune components of the tumor microenvironment. Interestingly, the immunological activity of RT does not exhibit linear dose-response correlation. Here, we discuss the mechanisms whereby RT alters the capacity of the immune system to recognize and eliminate irradiated cancer cells, either as an “on-target” or as on “off-target” effect. In particular, we discuss the antagonism between the immunostimulatory and immunosuppressive effects of RT as we delineate combinatorial strategies to boost the former at the expenses of the latter.

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Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

Cited by 658 publications

References 305 publications

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

Immune recognition of irradiated cancer cells

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