Role of 5-Fluorouracil in the modulation of anticancer immune responses: Molecular mechanisms and identification of novel therapeutic targets – RFAT

Use of cellular and molecular biology techniques as well as preclinical tumor models (see Bruchard et al, Nature Medicine, 2013).

We were able to demonstrate that 5 Fluorouracil leads to the production of IL-1b by MDSC via an activation of the inflammasome NLRP3. This is due to the permeabilisation of lysosomes by 5FU and the release of cathepsin B which then activates directly NLRP3. The secretion of IL-1 is at the origin of a Th17 polarization of the CD4 T cell immune response and of IL-17 production that is detrimental for antitumor response.
Therapeutic agents targeting IL-17 or IL-1 are capable of enhancing the effect of 5 fluorouracil in vivo. These data have just been published in Nature Medicine in 2013.

We are about to start a phase II clinical trial testing the potential benefit of combining 5-Fluorouracil and IL-1R antagonist in metastatic colorectal cancer patients. The trial will be performed at the Georges François Leclerc anticancer center in Dijon, France.

2013
Bruchard M*, Mignot G*, ... , Apetoh L*, Ghiringhelli F*. Chemotherapy-triggered cathepsin B release in myeloid-derivedsuppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med. 2013 Jan;19(1):57-64. (*Contributed equally)

2012
Martin F, Apetoh L, Ghiringhelli F. Controversies on the role of Th17 in cancer: a TGF-ß-dependent immunosuppressive activity? Trends Mol Med. 2012 Oct 17. pii: S1471-4914(12)

Hervieu et al. Dacarbazine-Mediated Upregulation of NKG2D Ligands on Tumor Cells Activates NK and CD8 T Cells and Restrains Melanoma Growth. J Invest Dermatol. 2012 Sep 6.

Ladoire et al. FOXP3 expression in cancer cells and anthracyclines efficacy in patients with primary breast cancer treated with adjuvant chemotherapy in the phase III UNICANCER-PACS 01 trial. Ann Oncol. 2012 Oct;23(10):2552-61.

Chalmin F*, Mignot G*, ... , Apetoh L*, Rébé C*, Ghiringhelli F*. Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity. 2012 Mar 23;36(3):362-73. (*Contributed equally)

2011
Martin F, Apetoh L, Ghiringhelli F. Role of myeloid-derived suppressor cells in tumor immunotherapy. Immunotherapy. 2012 Jan;4(1):43-57.

Pot C*, Apetoh L*, Awasthi A, Kuchroo VK. Induction of regulatory Tr1 cells and inhibition of T(H)17 cells by IL-27. Semin Immunol. 2011 Dec;23(6):438-45.

Apetoh L*, Végran F*, Ladoire S, Ghiringhelli F. Restoration of antitumor immunity through selective inhibition of myeloid derived suppressor cells by anticancer therapies. Curr Mol Med. 2011 Jul 1;11(5):365-72. (*Contributed equally)

Ma et al. Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. J Exp Med. 2011 Mar 14;208(3):491-503.

Apetoh L, Locher C, Ghiringhelli F, Kroemer G, Zitvogel L. Harnessing dendritic cells in cancer. Semin Immunol. 2011 Feb;23(1):42-9. Review.

Primary tumors are currently treated by a combination of therapies including, in most cases, surgery, local radiotherapy, and adjuvant chemotherapy. Even when the tumor has apparently been defeated, micrometastases of dormant tumor cells frequently lead to tumor relapse and final therapeutic failure. Accumulating evidence indicates that the innate and adaptive immune systems can make a crucial contribution to the antitumor effects of conventional chemotherapy-based cancer treatments. However, the tumor-mediated immunosuppression of the host often limits the initiation of an effective anticancer immune response. Therefore, to defeat cancer, it is essential to relieve host immunosuppression to unleash an immune response that eradicates residual tumor cells. We have identified that 5-Fluorouracil (5-FU), a pyrimidine analog that is mainly used in the treatment of breast and colon cancer, has a superior and selective ability to deplete Myeloid derived suppressor cells (MDSC) in vivo. The elimination of MDSC by 5-FU partly restored anticancer responses and improved 5-FU therapeutic effect. However, our preliminary data indicate that an additional molecular pathway activated by the 5-FU-mediated cell death of MDSC limits the efficacy of 5-FU and contributes to immune evasion. Specifically, we hypothesize that 5-FU triggers an inflammatory, caspase-1-dependent cell death of MDSC, which supports the IL-1ß-mediated polarization of intratumor Th17 cells that impair the development of anticancer responses. Thus, by identifying the molecular mechanisms by which 5-FU affects MDSC, this project ultimately aims at unraveling new molecular targets that could be modulated to achieve optimal anticancer responses.