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ABSTRACT
The immune system avoids oncogenesis and slows down tumor progression through a mechanism called immunosurveillance. Nevertheless, some malignant cells manage to escape from immune control and form clinically detectable tumors. Tetraploidy, which consists in the intrinsically unstable duplication of the genome, is considered as a (pre)-cancerous event that can result in aneuploidy and contribute to oncogenesis. We previously described the fact that tetraploid cells can be eliminated by the immune system. Here, we investigate the role of different innate and acquired immune effectors by inoculating hyperploid cancer cells into wild type or mice bearing different immunodeficient genotypes (Cd1d−/−, FcRn−/−, Flt3l−/−, Foxn1nu/nu, MyD88−/−, Nlrp3−/−, Ighmtm1Cgn, Rag2−/−), followed by the monitoring of tumor incidence, growth and final ploidy status. Our results suggest that multiple different immune effectors including B, NK, NKT and T cells, as well as innate immune responses involving the interleukine-1 receptor and the Toll-like receptor systems participate to the immunoselection against hyperploid cells. Hence, optimal anticancer immunosurveillance likely involves the contribution of multiple arms of the immune system.
Abbreviations
| CALR | = | calreticulin |
| CTLA-4 | = | cytotoxic T lymphocyte – associated protein 4 |
| DC | = | dendritic cell |
| FcRn | = | neonatal Fc receptor |
| FELASA | = | Federation of European Laboratory Animal Science Association |
| Flt3l | = | ligand for the receptor tyrosine kinase 3 |
| FBS | = | fetal bovine serum |
| Ig | = | immunoglobulin |
| IL-1 | = | interleukin 1 |
| IL-1Ra | = | interleukin 1 receptor antagonist |
| IL-18 | = | interleukin 18 |
| IL-2R | = | interleukin 2 receptor |
| IL-4 | = | interleukin 4 |
| IFN-γ | = | interferon gamma |
| MHC | = | major histocompatibility complex |
| NK | = | natural killer cell |
| NKT | = | natural killer T cell |
| NLRP3 | = | NACHT, LRR and PYD domains-containing protein 3 |
| RAG-2 | = | recombinase activating gene 2 |
| PBS | = | phosphate-buffered saline |
| PFA | = | paraformaldehyde |
| Th | = | T helper type |
| TH1 cells | = | CD4+ T helper cells expressing IFN-γ |
| TLR | = | toll-like receptors |
| WT | = | wild type. |
| γc | = | cytokine receptor γ chain |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
GK is supported by the Comité de Charente-Maritime (équipe labelisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; the European Commission (ArtForce); the European Research Council (ERC); Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). LS is supported by the Institut national de la santé et de la recherche médicale (INSERM) and the Association pour la recherche sur le cancer (ARC) (PJA20151203519). We are indebted to Dr. Aitziber Buqué for her help in the analysis of tumor images. We appreciate the help from the Preclinical evaluation platform (PEP) in Gustave Roussy Campus Cancer, especially Dr. Patrick Gonin and Mrs. Olivia Bawa.