Bérengère Salomé, PharmD, PhD, graduated from the Université de Nantes (France) with a Pharmaceutical Doctorate and from the Université Paris Descartes with a Master in Immunology Research. She then moved to Lausanne (Switzerland) for her PhD, where she focused on the Innate Lymphoid Cell (ILC) roles in human cancer. During her doctoral studies, Bérengère demonstrated the impairment of a novel cytotoxic cell population at the interface between conventional ILCs and NK cells in Acute Myeloid Leukemia. She is now dissecting NK and T cell education in healthy donors and in cancer patients in order to optimize immunotherapeutic strategies.

Project 1 : HLA-E and NKG2A as a novel immune checkpoint axis to exploit for treatment of early-stage non-muscle invasive bladder cancer

More than 180,000 new bladder cancer cases are diagnosed each year worldwide. Intravesical Mycobacterium bovis Bacillus Calmette-Guérin (BCG) instillation is the standard therapy of non-muscle invasive bladder cancer, yet recurrence occurs in approximately 40% of treated patients. NK cells are essential for maintaining anti-tumor immunity and controlling for tumor recurrence after BCG therapy. The HLA-E/NKG2A pathway is a major driver of the NK education and HLA-E expression levels depend on the HLA-A and the HLA-B genotypes. Bérengère focuses on characterizing the HLA class I genotype contribution in predicting the response to BCG therapy in bladder cancer patients. This study is part of a collaboration with Dr. John Sfakianos (Department of Urology, Icahn School of Medicine at Mount Sinai).

The Milieu Intérieur consortium, led by the Institut Pasteur (France) and Genentech, has demonstrated that smoking, cytomegalovirus (CMV) infection, age and gender are strong contributors to human immune variation, based on flow cytometry data on 1,000 healthy donors. They have also conducted transcriptomic and proteomic analyses on blood of these donors, including in vitro stimulation with BCG . Through a collaboration with Institut Pasteur and Genentech, Bérengère is therefore using these datasets to evaluate the contribution of the HLA class I and KIR genotypes on the in vitro immune response to BCG stimulation in healthy donors.

She is also using datasets derived from HTG multiplexed in situ hybridization, Olink Proteomics, CyTOF, single-cell RNA sequencing and Imaging Mass Cytometry technologies to analyze the effect of the HLA class I and KIR genotypes as well as CMV serostatus on the immune response to in vivo BCG therapy in non-muscle invasive bladder cancer patients.

Project 2 : Characterizing the influence of the HLA class I and KIR genotypes on the efficacy of anti-NKG2A immunotherapy

NKG2A is an immune checkpoint that is increased in the tumor micro-environment on CD8 T cells. NKG2A blocking antibody, monalizumab, triggers CD8 T cell (and NK cell) functions and decreases tumor growth in mouse models. NKG2A exerts its regulatory function as a heterodimeric complex with another c-type lectin-like receptor (CD94) by binding to HLA-E. The HLA-E/NKG2A pathway has become a major focus in settings of cancer immunotherapies as a large proportion of tumor infiltrating CD8 T cells that express PD-1 are co-expressing NKG2A, which may explain the poor overall efficacy of checkpoint blockade monotherapies. Through a collaboration with Astra Zeneca, Bérengère is focused on pre-clinical mechanistic studies to potentially ‘reposition’ combination immunotherapies targeting NKG2A- and PD-L1-blockade alongside intravesicle BCG therapy. This study is part of a collaboration with Dr. John Sfakianos and Dr. Nina Bhardwaj (Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai).

In this project, Bérengère is using CyTOF, Imaging mass cytometry, single-cell RNA sequencing and functional assays to evaluate the influence of the HLA class I and KIR genotypes on the in vitro restoration of human CD8 T cell functions by NKG2A blockade.

Project 3 :  Characterizing the effects of HLA class I and KIR genotypes on ILC/NK cell development in human tonsils

Innate Lymphoid cells (ILCs) are innate immune cells devoid of rearranged antigen receptors (TCR, BCR). They are divided into two groups : the cytotoxic NK cells and the helper ILC1, ILC2 and ILC3. Emerging data on the development of NK cells in humans suggests five discrete stages of development. In tonsils, stage 3 represents immature ILC/NK progenitors that can give rise to Stage 4a NK progenitors or to ILC2 and ILC3. Stage 4a is characterized by the acquisition of CD94 and NKG2A, Stage 4b by the acquisition of NKp80 and Stage 5 by the acquisition of CD16 and KIR receptors. During Bérengère’s doctoral studies, she uncovered a novel subset of NKG2A+ CD56+ ILC1-like cells that are related to Stage 4b NK cells and cytotoxic properties regulated by HLA-E/NKG2A and several activating receptors typically associated with Nk cell anti-tumor functions.

NK cells are educated through the HLA-E/NKG2A and the HLA-A,-B,-C/KIR pathway. Through a collaboration with Dr. Aharon Freud (Ohio State University) and Dr. Emily Mace (Columbia University), Bérengère is studying how NK and ILC progenitors develop under different HLA class I and KIR backgrounds and how this shapes the formation of the phenotypic and functional diversity within this repertoire of innate lymphoid cells. She is using CyTOF, single-cell RNA sequencing and imaging mass cytometry to identify the role of the HLA and KIR genotypes on the Stage 3-5 transitions of the ILC/NK cell development in tonsils. At each stage of development, Bérengère is characterizing their functional potential and their distribution and organization within tonsils. This work will provide the fundamental framework biology for future studies focused specifically on head and neck cancer but also allowing for an understanding of NK/ILC developmental intermediates that can be studied in many other tissues.