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Immunogenic death of colon cancer cells treated with oxaliplatin

Abstract

Both the pre-apoptotic exposure of calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death elicited by anthracyclins. Here, we show that both oxaliplatin (OXP) and cisplatin (CDDP) were equally efficient in triggering HMGB1 release. However, OXP, but not CDDP, stimulates pre-apoptotic CRT exposure in a series of murine and human colon cancer cell lines. Subcutaneous injection of OXP-treated colorectal cancer (CRC), CT26, cells induced an anticancer immune response that was reduced by short interfering RNA-mediated depletion of CRT or HMGB1. In contrast, CDDP-treated CT26 cells failed to induce anticancer immunity, unless recombinant CRT protein was absorbed into the cells. CT26 tumors implanted in immunocompetent mice responded to OXP treatment in vivo, and this therapeutic response was lost when CRT exposure by CT26 cells was inhibited or when CT26 cells were implanted in immunodeficient mice. The knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. In patients with advanced (stage IV, Duke D) CRC, who received an OXP-based chemotherapeutic regimen, the loss-of-function allele of TLR4 (Asp299Gly in linkage disequilibrium with Thr399Ile, reducing its affinity for HMGB1) was as prevalent as in the general population. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele. In conclusion, OXP induces immunogenic death of CRC cells, and this effect determines its therapeutic efficacy in CRC patients.

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Acknowledgements

We thank all the investigators who participated in the FFCD 2000–05 clinical trial; Pierre Laurent Puig for help with DNA extraction and storage; and Patrick Gonin and IGR animal facility for helping with mouse breeding. This study was supported by INSERM (AT); FRM (FS); Cancéropôle Ile-de-France, Institut National du Cancer, Fondation de France, Association Laurette Fugain, Cent pour Sang la Vie, Agence National de la Recherche, Association for International Cancer Research (AICR), and the European Commission (ApoSys, ChemoRes, Death-Train, RIGHT) (GK); la Ligue and FRM (LA); a fellowship from La Ligue (IM); a fellowship from ARC (MM).

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Correspondence to G Kroemer.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Tesniere, A., Schlemmer, F., Boige, V. et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29, 482–491 (2010). https://doi.org/10.1038/onc.2009.356

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