Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma

Amaravadi, Ravi K.; Yu, Duonan; Lum, Julian J.; Bui, Thi Ngoc Tuan; Christophorou, Maria A.; Evan, Gérard I.; Thomas-Tikhonenko, Andrei; Thompson, Craig B.

doi:10.1172/jci28833

Cited by 1,031 publications

(894 citation statements)

References 51 publications

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“…105 Other studies, however, support the use of autophagy inhibitors as potentiators of anticancer agents. 106,107 As an example, the mammalian target of rapamycin (mTOR) kinase inhibitor everolimus, which induces autophagy, prolonged the survival of patients affected by renal cell carcinoma in a phase-III clinical trial. 106 Interestingly, Michaud et al 108 reported that autophagy is dispensable for chemotherapy-induced TCD, but is required for its immunogenicity.…”

Section: Effects On Tumor Cells and On Tumor Microenvironmentmentioning

confidence: 99%

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

et al. 2013

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Conventional anticancer chemotherapy has been historically thought to act through direct killing of tumor cells. This concept stems from the fact that cytotoxic drugs interfere with DNA synthesis and replication. Accumulating evidence, however, indicates that the antitumor activities of chemotherapy also rely on several off-target effects, especially directed to the host immune system, that cooperate for successful tumor eradication. Chemotherapeutic agents stimulate both the innate and adaptive arms of the immune system through several modalities: (i) by promoting specific rearrangements on dying tumor cells, which render them visible to the immune system; (ii) by influencing the homeostasis of the hematopoietic compartment through transient lymphodepletion followed by rebound replenishment of immune cell pools; (iii) by subverting tumor-induced immunosuppressive mechanisms and (iv) by exerting direct or indirect stimulatory effects on immune effectors. Among the indirect ways of immune cell stimulation, some cytotoxic drugs have been shown to induce an immunogenic type of cell death in tumor cells, resulting in the emission of specific signals that trigger phagocytosis of cell debris and promote the maturation of dendritic cells, ultimately resulting in the induction of potent antitumor responses. Here, we provide an extensive overview of the multiple immune-based mechanisms exploited by the most commonly employed cytotoxic drugs, with the final aim of identifying prerequisites for optimal combination with immunotherapy strategies for the development of more effective treatments against cancer.

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Section: Effects On Tumor Cells and On Tumor Microenvironmentmentioning

confidence: 99%

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

et al. 2013

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“…Low levels of autophagic activity are observed under physiological conditions, while in tumor cells, autophagy promotes cell survival during the frequent nutrient restriction and hypoxia [49]. Autophagy was found to sustain the maintenance of cancer stem cell phenotype, and cooperates to chemo-and radio-resistance [50][51][52][53]. Inhibition of autophagy, on the contrary, increases chemo-and radio-sensitivity [54].…”

Section: How Low Ph May Contribute To Dormancy Of Tumor Cells Aciditymentioning

confidence: 99%

The acidic microenvironment as a possible niche of dormant tumor cells

Peppicelli

Andreucci

Ruzzolini

et al. 2017

Cell. Mol. Life Sci.

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“…80,81,82 Hence, more efforts should be made to elucidate the intricate interaction between autophagy inhibition and resulting effects on the immunogenicity.…”

Section: Autophagic Cell Deathmentioning

confidence: 99%

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

2013

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Apoptotic cell death generally characterized by a morphologically homogenous entity has been considered to be essentially non-immunogenic. However, apoptotic cancer cell death, also known as type 1 programmed cell death (PCD), was recently found to be immunogenic after treatment with several chemotherapeutic agents and oncolytic viruses through the emission of various danger-associated molecular patterns (DAMPs). Extensive studies have revealed that two different types of immunogenic cell death (ICD) inducers, recently classified by their distinct actions in endoplasmic reticulum (ER) stress, can reinitiate immune responses suppressed by the tumor microenvironment. Indeed, recent clinical studies have shown that several immunotherapeutic modalities including therapeutic cancer vaccines and oncolytic viruses, but not conventional chemotherapies, culminate in beneficial outcomes, probably because of their different mechanisms of ICD induction. Furthermore, interests in PCD of cancer cells have shifted from its classical form to novel forms involving autophagic cell death (ACD), programmed necrotic cell death (necroptosis), and pyroptosis, some of which entail immunogenicity after anticancer treatments. In this review, we provide a brief outline of the well-characterized DAMPs such as calreticulin (CRT) exposure, high-mobility group protein B1 (HMGB1), and adenosine triphosphate (ATP) release, which are induced by the morphologically distinct types of cell death. In the latter part, our review focuses on how emerging oncolytic viruses induce different forms of cell death and the combinations of oncolytic virotherapies with further immunomodulation by cyclophosphamide and other immunotherapeutic modalities foster dendritic cell (DC)-mediated induction of antitumor immunity. Accordingly, it is increasingly important to fully understand how and which ICD inducers cause multimodal ICD, which should aid the design of reasonably multifaceted anticancer modalities to maximize ICD-triggered antitumor immunity and eliminate residual or metastasized tumors while sparing autoimmune diseases.

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Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma

Cited by 1,031 publications

References 51 publications

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

The acidic microenvironment as a possible niche of dormant tumor cells

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

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