Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death

By N. Casares, M. Péquignot, A. Tesnière, François Ghiringhelli, S. Roux, N. Chaput, E. Schmitt, Ahmed Hamai, Sandra Hervás-Stubbs, M. Obeid and 8 more. Journal of Experimental Medicine, 2005

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Systemic anticancer chemotherapy is immunosuppressive and mostly induces nonimmunogenic tumor cell death. Here, we show that even in the absence of any adjuvant, tumor cells dying in response to anthracyclins can elicit an effective antitumor immune response that suppresses the growth of inoculated tumors or leads to the regression of established neoplasia. Although both antracyclins and mitomycin C induced apoptosis with caspase activation, only anthracyclin-induced immunogenic cell death was immunogenic. Caspase inhibition by Z-VAD-fmk or transfection with the baculovirus inhibitor p35 did not inhibit doxorubicin (DX)-induced cell death, yet suppressed the immunogenicity of dying tumor cells in several rodent models of neoplasia. Depletion of dendritic cells (DCs) or CD8+T cells abolished the immune response against DX-treated apoptotic tumor cells in vivo. Caspase inhibition suppressed the capacity of DX-killed cells to be phagocytosed by DCs, yet had no effect on their capacity to elicit DC maturation. Freshly excised tumors became immunogenic upon DX treatment in vitro, and intratumoral inoculation of DX could trigger the regression of established tumors in immunocompetent mice. These results delineate a procedure for the generation of cancer vaccines and the stimulation of anti-neoplastic immune responses in vivo.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e89db06973fee96969ecbabaaf742da71bfb89f8

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Citations in the corpus

Revisiting Interleukin-12 as a Cancer Immunotherapy Agent (2018, background): “In these mice, IL12 is combined with doxorubicin, a chemotherapy agent with multiple effects on the tumor tissue microenvironment that can help the antitumor immune response, such as immunogenic cell death of a fraction of tumor cells (2) and reduction of regulatory T cells and myeloid-derived suppr”
Immunological aspects of cancer chemotherapy (2008, background): “As a possible mechanism to account for the immune-mediated anticancer effects of anthracylines, it has recently been discovered that anthracyclines — unlike many other cytotoxic agents — can elicit immunogenic cell death (see below”
Mechanisms of pre‐apoptotic calreticulin exposure in immunogenic cell death (2009, methodology): “…579 Pre-apoptotic activation of apoptosis effectors is indispensable for CRT/ERp57 exposure MTX-induced immunogenicity requires the activation of cas- pases that are inhibited by the modified peptide Z-VAD-fmk or by the baculovirus-encoded inhibitor of apoptosis, protein p35 (Casares et al, 2005).”
Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. (2015, background): “…compromised: (1) by the ablation of specific T cell subsets (including CTLs and gd T cells), but not by the absence of NK cells and B lymphocytes (Casares et al., 2005; Ma et al., 2011b; Yamazaki et al., 2014); (2) when tumor infiltration by DCs is inhibited, for instance with anti-CD11b mAb…”
Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy (2007, background): “Depending on the cell death inducer, some types of tumor cell death can also induce an antitumor immune response, and this property can be exploited to break tumor-induced immune toleranc”
Immune parameters affecting the efficacy of chemotherapeutic regimens (2011, background): “Beyond the broad impact of chemotherapeutics on the propensity of cancer cells to undergo lysis, some antitumor agents can also trigger immunogenic tumor-cell death”
How Do Cytotoxic Lymphocytes Kill Cancer Cells? (2015, background): “These questions, which may seem trivial for the elimination of cancer cells, are important in the context of recent findings indicating that the subsequent response of the immune system against dying cells greatly depends on the way cells die, that is, if cell death is immunogenic or not (9, 10).”