Research
Immunity and cancer : N. Bonnefoy

While the immune system has long been considered to play its main role in the early surveillance against arising and nascent transformed cells, its immunnosuppressive functions and deleterious contributions to the control of the tumorigenesis process associated with disease progression and resistance to therapies remain less defined. While, unprecedented improvements in tumor control have been achieved with therapeutic blocking antibodies that release immune inhibitory checkpoints, such as monoclonal antibodies blocking the inhibitory PD-1/PD-L1 axis, it is now obvious that strong anti-tumor immune responses are observed only in a minority of patients, whereas innate or acquired resistance to immune checkpoints inhibitors (ICI) is common. Many efforts are therefore being made to identify new targets that activate, unleash or enhance anti-tumor immune responses.

In close collaboration with clinicians and industrials, our projects aim at 1/ identifying novel strategies to unleash anti-tumor immune responses, with a specific focus on immunosuppressive molecular and cellular mechanisms that contribute tumor escape to immune surveillance, 2/ characterizing tumor immune microenvironment associated with tumor progression and resistance to treatments and finally 3/ proposing novel immune-based therapeutic strategies founded on hypothesis-driven preclinical and clinical models.

Research programs under development are summarized below:

1- Exploring the tumor-promoting activity of IL-17B/IL-17RB axis

This research program focuses on the influence of a pro-inflammatory tumor microenvironment on tumor immune surveillance mechanisms, with particular interest for the pro-tumor functions of the cytokines of the interleukin 17 (IL-17) family. Indeed, following our demonstration that IL-17B promotes resistance to chemotherapeutic agents (Laprevotte E. et al 2017) and in close collaboration with OREGA-Biotech, one of our objectives is to better describe the pro-oncogenic potential of IL-17B. We aim to uncover the molecular and cellular mechanisms involved in this effect of IL-17B and ambition to obtain a proof of the concept of the use of anti-IL-17B mAbs as an attractive strategy for combined cancer therapy.

2- Exploring tumor-promoting activity of γδ T cells in pancreatic and breast cancers.

Much research efforts are currently focused on understanding the molecular mechanisms that govern the functional polarization of γδ T cells, and how tumor ecosystem could tilt effector γδ T cells towards a regulatory phenotype, or favor the recruitment and development of regulatory γδ T cell subsets, especially in breast and pancreatic cancers. Based on recent published data, including ours, we aim at providing a better characterization and understanding of regulatory γδ T cell subpopulations in cancer. Our main objectives are:

1- To decipher the molecular mechanisms that account for the suppressive functions of human CD73+ γδ T cells we recently identified (Barjon C. et al, 2017).

2- To characterize CD73+ γδ T cell population, through the identification of its specific transcriptomic and phenotypic signatures and to interrogate its cellular network by imaging mass cytometry within biopsies from cancer patients to decipher their role regarding tumor stage or immune suppression.

3- Exploring tumor-promoting activity of neutrophils in lung cancer

Myeloid cells have emerged as key regulators of cancer growth, among them we recently demonstrated that neutrophils are a major immune contributor in disease progression in lung cancer (Faget J et al., 2017). These cells promote resistance to immunotherapy by inducing immune exclusion and remolding tumor vasculature. To reinforced the understanding of pro-tumoral functions of neutrophils, we aim at:

1- Mapping cellular network together with the immune signature and signaling by imaging mass cytometry in lung tumors using primarily the Kras^LSL-G12D/WT; p53^flox/flox model of lung cancer. We expect so, to identify new targetable pathways to inhibit neutrophil mediated tumor promotion.

2- Developing innovative approaches to refine neutrophil depletion methods and evaluating the potential therapeutic activity of antibody drug conjugates specific for neutrophils.

3- Identifying epigenetic and transcriptomic modifications in neutrophils and their progenitors during lung cancer development.

4- Comprehensive study of cervix tumor immune microenvironment to improve radiotherapy

This research program is focused on the impact of radiotherapy on the immune microenvironment of the tumor and developed in close collaboration with the radiotherapy department of the ICM. Currently, radio-chemotherapy is the standard treatment for locally advanced cervical cancer, however, about 20% of patients have primary resistance to treatment and about 50% of the responder relapse after 5 years, demonstrating the need for new therapeutic approaches. One of our objectives is to decipher the contribution of the immune system to the effectiveness of radiotherapy by a fine characterization of the tumor immune microenvironment in in vivo preclinical models and in patients. This work would help 1/ to identify new immune signatures predicting the treatment response and 2/ to design new therapeutic strategies based on the combination of radiotherapy with immunotherapies targeting new "immune checkpoints".

5- Targeting the adenosine pathway to improve Immunomodulatory effects of tumor-targeting mAbs.

Using the B16F10 melanoma preclinical model, we demonstrated the immunomodulatory potential of the anti-TYRP-1 mAb, TA99, leading  to 30% of complete tumor eradication associated with a long-term protective memory immune response. We further provided evidence that, PD-1 axis blockade at the time of tumor emergence can efficiently boost the host anti-tumor immune response initiated several weeks before by the TA-targeting mAb (They L. et al, 2017). However, the synergy observed between TA99 and anti-PD-1 mAbs was not sufficient to induce complete tumor regressions, suggesting the implication of other immune suppressive pathways. Having shown a strong expression of the CD39 and CD73 ectonucleotidases within progressing tumors, we propose to assess the impact of CD39 or CD73 blockade, combined or not with PD-1 inhibition, to prevent tumor escape to TA99 treatment. Following our previous results with ICI and chemotherapy, such results would extend the concept that targeting the immunosuppressive adenosine pathway is beneficial and improves protective anti-tumor immunity.