Research
Immunity and cancer : N. Bonnefoy

The development of immunotherapies aimed at inducing an effective anti-tumor immune response has revolutionized the treatment of cancer patients for more than 15 years.  However, a major challenge remains to better understand the relationship between cancer cells and cells of the immune system in order to increase the success rate of these treatments. Our team is particularly committed to unraveling the molecular and cellular immunosuppressive mechanisms that contribute to tumor escape from immune surveillance. We are investigating the architecture of the tumor microenvironment and the local and systemic immune changes associated with tumorigenesis in various preclinical models and in patients . In close collaboration with clinicians and industry partners, our goal is to identify novel therapeutic targets and biomarkers and to provide proof-of-concept for novel therapeutic strategies to improve patient response rates to anticancer therapies.

THEME 1: TUMOR MICROENVIRONMENT (TME) IMMUNOSUPPRESSIVE NICHES

Axis 1 : Immunosuppressive niches in ovarian cancer (Principal investigators: V Lafont & M Chauvin)

Having demonstrated that the density of regulatory CD73+ γδ T cells within the TME is associated with poor survival in ovarian cancer, we are deciphering their contribution to the establishment of an immunosuppressive niche in ovarian tumor and the mechanisms involved. In a complementary manner, we recently showed that cancer-associated mesothelial cells (CAMCs) reprogram immune TME towards pro-tumoral functions through the secretion of anti-Müllerian hormone or follistatin. To decipher the role of mesothelial cells in the TME, we are using mouse models of high grade serous ovarian cancer, as well as conditional and inducible CAMC-CRE-ER/Lox models allowing to trace or deplete pro-tumoral CAMCs in ovarian TME and heterotypic 3D spheroid model to address the mechanistic aspects of CAMCs on immune cells infiltration. These models should allow to identify specific biomarkers and to understand the immunomodulatory functions of CAMCs.

Axis 2 : Metabolic and immune tumor heterogeneity in esophageal adenocarcinoma (Principal investigators : HA Michaud & A Adenis)

Together with Le Cam’s team, we have developed a comprehensive and broad analysis of the TME based on innovative proteomic and transcriptomic spatial approaches allowing deep immunophenotyping and metabolic profiling. We apply such expertise to analyze esophageal adenocarcinoma, one of the most complex cancer types in terms of resistance. By interrogating spatial data in pre- and post-treatment tumor tissues, we hope to identify cell communities associated with treatment response and tumor progression. Targeting cell populations or metabolic pathways associated with treatment resistance will then be tested using immunocompetent or humanized mouse models and patient-derived organoids.

Axis 3: Exploring the tumor-promoting activity of IL-17B/IL-17RB axis (Principal investigator : N Bonnefoy)

This research program focuses on the influence of a pro-inflammatory tumor microenvironment on tumor immune surveillance mechanisms, with particular interest in the pro-tumor functions of the interleukin-17 (IL-17) family of cytokines. Indeed, following the demonstration that IL-17B promotes resistance to chemotherapeutic agents, we aim to better characterize the pro-oncogenic potential of IL-17B. We aim to elucidate the molecular and cellular mechanisms involved in this effect of IL-17B and to obtain a proof of concept for the use of anti-IL-17B antibodies as an attractive strategy for combined cancer therapy.

THEME 2: CANCER REMOTE IMMUNE ALTERATIONS

Axis 1: Predicting immune checkpoint responses by analyzing circulating neutrophil as biomarker (Principal investigator: J Faget)

We aim to explore local and systemic alterations of the immune system imposed by cancer development, progression and treatment through the prism of neutrophil biology in lung cancer. Our working hypothesis is that specific neutrophil biogenesis alterations might associate with patients’ response to therapy. This project relies on the implementation of new tools such as CITE-single-cell RNA sequencing, Infinity-Flow, and epigenetic profiling of the neutrophil genome. Using blood samples from lung cancer patient at diagnostic, we are searching for predictive biomarkers of the response to immune checkpoint blockade and how they associate with the architecture of the tumor microenvironment.

Axis 2 : Remote immune alteration in the context of lung cancer (Principal investigator: J Faget)

In this emerging axis, our goal is to develop a holistic approach exploring major immune-related physiological changes occurring in patients (cachexia, treatment adverse events) as a long-term perspective. We are exploring local and systemic alterations of the immune system imposed by cancer development, progression and treatment in transgenic autochthonous and transplantable mouse models of lung cancer. Our goal is to modulate cancer cell characteristics (oncogenic signaling, metabolism, tumor suppressor gene alteration, innate immune pathway) to determine how it associates with specific systemic alteration of the immune system and body performance score. 

THEME 3: PROOF OF CONCEPT FOR INNOVATIVE IMMUNE-BASED THERAPIES

Axis 1 : Intra-tumoral drug delivery through BEPO® polymers (Principal investigator : L Gros)

Together with MedinCell pharmaceutical company, we delivered the first PoC in oncology that controlled local delivery of immunomodulatory drugs through BEPO® technology provides clinical benefit while reducing systemic toxicities using murine melanoma models. We now aim to elucidate the mechanisms associated with the protective effects of drug delivery in combination with a tumor targeting antibody and to validate the beneficial effect of local delivery of immunomodulatory molecules in order to reach the first preclinical regulatory studies. Then, we will extend the principle of local delivery based on the BEPO® technology to peritoneal carcinosis arising from primary ovarian, colon or pancreatic cancer tumors, which are particularly resistant to current therapies. We are focusing our studies on known molecules that are either marketed or in clinical development.

Axis 2 : Development of personalized RNA-based cancer vaccine (Principal investigator : J Faget & N Bonnefoy within the TumorOUT TRANSCAN-3 European consortium)

This research program is based on innovative PBAE nanoparticles (NPs) which have the property to encapsulate and transfect nucleic acids. These NPs are designed to specifically transfect neutrophils, macrophages, dendritic cells and modified to cross the lung mucosa. We are combining both antigen-mRNA and siRNA targeting STING signaling inhibitory genes (Trex1 and LysRS) or CD39 to impair adenosine production, with the aim of stimulating innate immune signaling by tumor and lung myeloid cells simultaneously transfected with a model tumor antigen (Ova-mRNA). We are working on the preclinical evaluation of this innovative RNA-vaccine strategy by taking advantage of our lung cancer transplantable and autochthonous mouse models, engineered to specifically express Ova into the cancer cells.

Axis 3 : Antibody-armed γδ T cells for innovative cell therapies (Principal investigator : V Lafont)

Based on the ability of cytotoxic γδ T cells to express CD16 Fcγ receptor we proposed an innovative strategy to exploit their ADCC capability using anti-tumor antibodies. We have shown that γδ T cells armed with tumor-specific antibodies eliminate tumor cells in vitro. Next steps will be to demonstrate this ability in the appropriate preclinical models. While mouse models, such as patient-derived xenograft models remain pivotal for the final POC in this project, we recently introduced more ethically sustainable approaches through the development in vitro heterotypic spheroid models. This research program represents a new direction for our team. We expect it could provide a new approach to use γδ T cells in cell therapy without requiring their genetic engineering and pave the way to the development of refined immunotherapies.