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Our project aims to understand the mechanisms that lead to the blockade of the anti-tumor immune response in order to identify new targets and to develop combined innovative therapeutic approaches.
A postdoctoral position is available to work specifically on pancreatic cancers (PC) that do not respond to immunotherapies with the aim to develop combined therapeutic approaches based on the team's expertise. Indeed, our recent works demonstrated that TNFR2, a TNF-receptor was preferentially expressed by regulatory T cells and that blocking this pathway resulted in Treg non-functionality (Leclerc et al. Blood 2016). We also recently identified and developed a nucleolin antagonist that normalizes pancreatic cancer tumor vessels (Diamantopoulou, Oncotarget 2017, Gilles, Cancer research 2016).
The key question addressed by the Postdoc will be to understand why PD1/PDL-1 or CTLA4 immune checkpoint inhibitors (ICIs) that have some beneficial effects in melanoma or lung cancers are inefficient in digestive cancers and notably in PC. Preclinical and clinical evidences suggest that only patients who have T-cell inflamed tumors respond to ICI monotherapy. Endogenous tumor-reactive T cells present within the human PDA tumor microenvironment have to be reactivated. However, ICIs failed in PC and one reason could be the highly immunosuppressive tumor microenvironment leading to exclusion of cytotoxic T lymphocytes from the tumor. Moreover, tumor vessels display abnormal structure and function leading to impaired oxygen, nutrient, and drug delivery that in turn favors immunosuppressive cells, and resistance to activated cytotoxic T-cells infiltration and immunotherapy.
Postdoc will have to:
The main objectives of the team is to identify new mechanisms and therapies that i) inhibit immune response in transplantation to promote immune tolerance thus preventing organ rejection or GVHD and ii) improve sensitivity of anti-cancer immunotherapy through manipulating the tumor microenvironment (TME). Our work has been mostly performed in mice but was also translated in several clinical trials in both transplantation and cancer. An important limitation we are facing in the development of anti-cancer therapy approaches is due to insufficiently relevant and easy to operate experimental models. We developed unique models allowing evaluating human tumor growth confronted to an immune system syngeneic to the tumor. We are working in close interactions with clinical departments and are leading the center for clinical investigation in biotherapy, a platform dedicated to early phase clinical trials developed in our research team.