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Vacchelli, Erika; Senovilla, Laura; Eggermont, Alexander M.M.; Fridman, Wolf‐Herman; Galon, Jérôme; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

doi:10.4161/onci.23510

Cited by 155 publications

(59 citation statements)

References 96 publications

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“…In line with this notion, ATP is essential for the accumulation of monocytic precursors within the tumor bed as well as for their local differentiation into dendritic cell-like APCs (3). Thus, shortly (24-72 hours) after the administration of immunogenic chemotherapy (11)(12)(13), ATP levels increase in the tumor interstitium as a consequence of the apoptotic demise of cancer cells. Of note, autophagy is required for such an immunogenic cell death-associated release of ATP to be optimal (8).…”

Section: Introductionmentioning

confidence: 99%

CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy

et al. 2014

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The therapeutic efficacy of anthracyclines relies, at least partially, on the induction of a dendritic cell-and T-lymphocyte-dependent anticancer immune response. Here, we show that anthracycline-based chemotherapy promotes the recruitment of functional CD11bpresenting cells (APC) into the tumor bed, but not into lymphoid organs. Accordingly, draining lymph nodes turned out to be dispensable for the proliferation of tumor antigen-specific T cells within neoplastic lesions as induced by anthracyclines. In addition, we found that tumors treated with anthracyclines manifest increased expression levels of the chemokine Ccl2. Such a response is important as neoplasms growing in Ccl2 À/À mice failed to accumulate dendritic cell-like APCs in response to chemotherapy. Moreover, cancers developing in mice lacking Ccl2 or its receptor (Ccr2) exhibited suboptimal therapeutic responses to anthracycline-based chemotherapy. Altogether, our results underscore the importance of the CCL2/CCR2 signaling axis for therapeutic anticancer immune responses as elicited by immunogenic chemotherapy. Cancer Res; 74(2); 436-45. Ó2013 AACR.

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Section: Introductionmentioning

confidence: 99%

CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy

et al. 2014

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“…However, a few chemotherapeutics, including anthracyclines, 7,8 OXA, 14 cyclophosphamide, 15 and -to some extent -microtubular inhibitors, 16 as well as cardiac glycosides, [17][18][19] potently do so. 20,21 Such chemicals appear to be particularly efficient at inducing a pre-mortem endoplasmic reticulum (ER) stress response and autophagy. ER stress culminates in the translocation of the ER chaperone calreticulin (CRT) to the cell surface, thereby generating an 'eat-me' signal for DCs.…”

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confidence: 99%

Molecular mechanisms of ATP secretion during immunogenic cell death

et al. 2013

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The immunogenic demise of cancer cells can be induced by various chemotherapeutics, such as anthracyclines and oxaliplatin, and provokes an immune response against tumor-associated antigens. Thus, immunogenic cell death (ICD)-inducing antineoplastic agents stimulate a tumor-specific immune response that determines the long-term success of therapy. The release of ATP from dying cells constitutes one of the three major hallmarks of ICD and occurs independently of the two others, namely, the pre-apoptotic exposure of calreticulin on the cell surface and the postmortem release of high-mobility group box 1 (HMBG1) into the extracellular space. Pre-mortem autophagy is known to be required for the ICD-associated secretion of ATP, implying that autophagy-deficient cancer cells fail to elicit therapy-relevant immune responses in vivo. However, the precise molecular mechanisms whereby ATP is actively secreted in the course of ICD remain elusive. Using a combination of pharmacological screens, silencing experiments and techniques to monitor the subcellular localization of ATP, we show here that, in response to ICD inducers, ATP redistributes from lysosomes to autolysosomes and is secreted by a mechanism that requires the lysosomal protein LAMP1, which translocates to the plasma membrane in a strictly caspase-dependent manner. The secretion of ATP additionally involves the caspase-dependent activation of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1)-mediated, myosin II-dependent cellular blebbing, as well as the opening of pannexin 1 (PANX1) channels, which is also triggered by caspases. Of note, although autophagy and LAMP1 fail to influence PANX1 channel opening, PANX1 is required for the ICD-associated translocation of LAMP1 to the plasma membrane. Altogether, these findings suggest that caspase-and PANX1-dependent lysosomal exocytosis has an essential role in ATP release as triggered by immunogenic chemotherapy.

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“…Although the methods that lead to the identification of ICD inducers can be criticized (and actually may fail to identify ICD inducers) [7, 8], these results support the contention that FDA-approved anticancer agents have a higher chance to elicit ICD than the drug candidates from the NCI (see Table 1 for statistical analyses). How can this difference be explained?…”

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confidence: 75%