Team ROUAS-FREISS
HLA and Immune Tolerance in Oncology and TransplantationLearn more about the team
Our research team is organized around three groups with complementary expertise, united by the study of classical and non-classical HLA molecules — central elements of the immune response in transplantation and oncology.
The team’s work addresses HLA molecules according to three axes:
- HLA molecules as peptide presenters, by analyzing the processes of generation, modulation, and TCR recognition of antigenic peptides, with the aim of contributing to the development of anti-cancer vaccines and new immunotherapy strategies.
- HLA molecules as antigenic targets in the context of graft-induced T and B cell alloreactivity, with the goal of preventing rejection and optimizing organ allocation, while developing therapeutic approaches targeting anti-HLA antibodies.
- The HLA-G molecule as a major driver of immune tolerance induction, with a view to exploiting its immunomodulatory properties to limit graft rejection and to better understand — and potentially counter — tumor escape mechanisms.
All projects developed within the team converge toward common translational objectives and challenges:
- In oncology, to contribute to the development of innovative therapeutic strategies based on biomarker identification, the design of therapeutic antibodies, and the emergence of new targeting molecules aimed at immune interactions.
- In transplantation, to improve graft acceptance, refine the prediction and management of rejection, and promote more personalized medicine for the benefit of transplant patients.
The team’s dynamic is built on the sharing of cutting-edge methodologies and integrative approaches, including microfluidic chip technologies, spectral cytometry, and bioinformatics tools dedicated to the analysis, integration, and modeling of complex data.
Research Axes
Group of Robin FAHRAEUS / Sébastien APCHER
Axis 1: Identification and characterization of peptides derived from non-canonical translation of cellular mRNAs as a novel source of MHC class I-presented antigens
Robin FAHRAEUS
This project studies the non-canonical translation mechanisms leading to the production of PTPs (Pioneer Translation Products). These PTPs constitute a preferential source of antigenic peptides for MHC class I presentation and play a determining role in the activation of CD8⁺ T lymphocytes. Their characterization opens up new perspectives in immuno-oncology, autoimmune diseases, and viral infections by identifying novel exploitable antigens and proposing strategies aimed at enhancing the immune visibility of modified cells.
Axis 2: Development of multi-epitope vaccines in oncology
Sébastien APCHER
Although nearly 98% of the human genome is traditionally considered non-coding, these regions constitute a major and still largely unexplored source of tumor-specific antigens. Cancer cells indeed express numerous peptides derived from regions of the genome that are usually poorly studied, which are likely to be presented by major histocompatibility complex (MHC) molecules and recognized by cytotoxic T lymphocytes.
This research axis aims to explore this “dark genome,” in addition to conventional coding regions, in order to substantially broaden the repertoire of tumor peptides available for the design of multi-epitope vaccines.
By expanding the exploitable antigenic space, this approach makes it possible to envision broader, more robust vaccine strategies that are potentially less susceptible to tumor escape mechanisms, thereby contributing to the development of new generations of anti-cancer vaccines.
More axis
Axis 3: Identification and development of novel compounds capable of enhancing the antitumor immune response
Sébastien APCHER
The goal of this project is to enhance the recognition of cancer cells by the immune system by pharmacologically stimulating the expression of tumor neo-antigens through inhibition of the spliceosome, a macromolecular complex involved in the removal of introns from precursor mRNAs. Spliceosome modulation induced by these treatments not only quantitatively alters certain epitopes expressed on the cell surface, but above all qualitatively generates new antigens specific to treated tumor cells. These neo-antigens thus promote more efficient and more selective recognition of cancer cells by the immune system, paving the way for the development of innovative vaccine strategies in oncology.
Axis 4: Development of next-generation antibody-drug conjugates (ADCs)
Sébastien APCHER
Antibody-drug conjugates (ADCs) represent an innovative therapeutic strategy that combines the high specificity of monoclonal antibodies with the potent cytotoxic activity of small pharmacological molecules. This approach enables selective targeting of tumor cells, optimizing antitumor efficacy while limiting systemic exposure and toxicity to healthy tissues. In this project, we aim to develop ADCs using novel spliceosome inhibitory molecules as therapeutic agents, coupled to monoclonal antibodies directed against innovative tumor targets, notably the HLA-G monoclonal antibody. This strategy aims to enhance antitumor efficacy while improving the tolerability profile of treatments, opening new perspectives in oncology.
Group of Jean-Luc TAUPIN
Solid organ transplantation is the reference treatment for end-stage organ failure, but graft rejection remains frequent. Antibody-mediated humoral rejection is the leading identified cause of organ transplant failure. Donor-specific anti-HLA antibodies (DSAs), whether pre-existing or induced after transplantation, are central markers and direct contributors to rejection by participating in T and B cell alloreactivity against the graft.
Axis 1: Biological and clinical impact of anti-HLA antibodies
Jean-Luc TAUPIN
Longitudinal DSA monitoring is a central tool in the management of transplant patients, but identifying truly pathogenic DSAs remains a major challenge. This project focuses on the fine characterization of DSAs in terms of recognized epitopes, shared eplets, and the alloreactive capacity specific to each HLA locus. One approach in the project is to use bioinformatic tools for HLA structure modeling to quantify the epitopic differences induced by donor/recipient polymorphisms. The goal is to contribute to a more precise evaluation of the immunological risk in transplant patients, with the aim of improving rejection prediction and guiding DSA-specific therapeutic strategies.
Group of Nathalie ROUAS-FREISS
Historically, this group was established at Saint-Louis Hospital by the CEA in 1991 as the Service de Recherches en Hémato-Immunologie (SRHI). It remains a unit affiliated with the Institut de Biologie François Jacob (CEA – Fundamental Research Division)
Axis 1: Positioning HLA-G as a new therapeutic target in tumor immunotherapy
Joel LEMAOULT – Jules RUSSICK – Nathalie ROUAS-FREISS
Development of new methodological approaches
The team has developed a 3D model for studying tumor cell/immune microenvironment interactions (spheroids) on a microfluidic chip. This model makes it possible to generate tumor avatars from cell lines or primary patient cells and to test their response to new therapeutic strategies (monotherapy, combined, or sequential) tailored to each patient, paving the way for personalized medicine.
Study of the antitumor function of intratumoral ILT2+ cells and their inhibition by HLA-G+ tumors
Through spectral cytometry studies (>35 markers) on patient cohorts, combined with RNA sequencing analyses, the team has described several sub-populations of ILT2+ CD8+ T lymphocytes that (i) constitute a reservoir of cytotoxic cells currently unexploited; and (ii) correlate with response to immunotherapies.
Definition of new therapeutic strategies
The team is developing new therapeutic strategies targeting HLA-G. It is notably evaluating the possibility of using bispecific antibodies, monoclonal antibodies, or peptides targeting HLA-G+ tumor cells and/or ILT2+-expressing immune cells.
Axis 2: Positioning HLA-G as a diagnostic marker of graft stability and an anti-rejection therapeutic tool in allogeneic therapies
Nathalie ROUAS-FREISS – Joel LEMAOULT – Jules RUSSICK
Since our first description of HLA-G expression in the context of cardiac transplantation in 2000, we have demonstrated that following solid organ transplantation (heart, lung, kidney, and liver), HLA-G expression is significantly observed in stable patients but not in those undergoing rejection. We observed a decrease in anti-HLA antibodies — known to be involved in allograft rejection — in HLA-G+ recipients. These studies have led to the consideration of HLA-G as a marker for identifying patients at low risk of rejection and as a therapeutic target in the definition of new anti-rejection treatments.
Role of the HLA-G molecule in lung transplantation as a predictive marker of graft survival and anti-rejection therapeutic target
After lung transplantation (LTx), vital prognosis is associated with the development of chronic rejection in the form of bronchiolitis obliterans syndrome. It is therefore important to have predictive markers of graft evolution. We had previously shown that HLA-G expression by the grafted tissue is associated with allograft acceptance. With a view to identifying non-invasive markers, we recently described (i) that an increased proportion of peripheral CD4+CD57+ILT2+ T lymphocytes during the first year following LTx (Brugière, JHLT 2022 and CEA-FOCH patent), and (ii) increased plasma levels of vesicular HLA-G (CEA-FOCH patent) allow distinction between patients who will subsequently undergo rejection and those who will remain stable 3 years after transplantation. The current project aims to explore the nature, origin, function, and clinical use of these HLA-G-harboring extracellular vesicles (HLA-G+ EVs), based on the hypothesis that they originate from the graft, are tolerogenic, and could serve as a non-invasive predictive marker as well as a novel therapeutic tool against rejection. This project is conducted in collaboration with (i) Foch Hospital (Olivier Brugière, LTx department, access to the national multicenter COLT cohort) and (ii) the Laboratory of Particles and Complex Systems at the Faculté des Saints-Pères (Florence Gazeau), an expert in EV biology and therapeutic use.
HLA-G and allogeneic cell therapy
This project builds on our recent findings on the role of HLA-G in enabling primary culture keratinocytes to acquire immunomodulatory properties (Mestrallet, Cells 2021 and Front Immunol 2022). We are currently studying HLA-G-mediated immunomodulation to improve the tolerance of autologous skin grafts, which are generally performed in an inflammatory context, or allogeneic bio-bandages, which face immune rejection. The goal is the design of a next-generation bio-engineered composite skin with superior immune tolerance compared to current graft models. This approach aims to leverage the tolerogenic properties of HLA-G. This project brings together teams of experts in HLA-G immunology (our team), preclinical (porcine) and clinical graft studies (Alexandre Lellouch, Tenon Hospital, Paris), and skin replacement (JJ Lataillade and Stéphane Banzet, IRBA/CTSA, Percy Hospital). Building on the work accomplished and experience gained during this first tissue engineering project with HLA-G, we aim in the future to transpose this approach in order to obtain tolerogenic solid organs expressing HLA-G.
Team members
Olivier BRUGIÈRE
MD PhD, PU-PH / Respiratory Medicine Department
Publications
2026 Am J Obstet Gynecol.
Immune tolerance breakdown in pregnancy: transplantation parallels in chronic intervillositis and villitis of unknown etiology
Hannoun P, Rabant M, Usureau C, Taupin JL, Zuber J, Benachi A.
View2026 Am J Transplant
Partial endothelial-to-mesenchymal transition associates with endothelial human leukocyte antigen II expression and precedes the development of de novo donor-specific anti-human leukocyte antigen antibodies in kidney recipients experiencing a delayed graft function
Xu-Dubois YC, Taupin JL, Dao M, Luque Y, Ahmadpoor P, Louis K, Devriese M, Mohamadou I, Snanoudj NA, Brocheriou I, Buob D, Francois-Pradier H, Rondeau E, Galichon P, Hertig A.
View2026 Cell.
HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion
Yoav Chemla, Orit Itzhaki, Stav Melamed, Chen Weller, Yuval Sade, Paulee Manich, Keren Reshef, Nicolas Xenidis, Avishai Maliah, Gilad Levy, Roma Parikh, Osnat Bartok, Opal Levy, Itay Tal, Gal Aziel, Abraham Nissani, Sharon Yunger, Daniela Likonen, Vitaly Kliminsky, Tamar Golan, Coralie Capron, Valentina Ace, Ronen Levy, Diana Rasoulouniriana, Zohar Eyal, Yuval Barzilay, Roi Balaban, Aseel Khateeb, Rami Khosravi, Amir Grau, Tamar Ziv, Polina Greenberg, Dvir Netanely, Hananya Vaknin, Xunwei Wu, Yael Amitay, Ronen Brenner, Julia María Martínez Gómez, Dov Hershkovitz, Tal Yardeni, Valentina Zemser‑Werner, Oren Kobiler, Yael Friedmann, David Bassan, Ron Shamir, Lea Eisenbach, Nadine Santana‑Magal, Michael Milyavsky, Galit Eisenberg, Leeat Keren, Merav Cohen, Dvir Gur, Boaz Barak, Michal Lotem, David Sprinzak, Shoshana Greenberger, David Fisher, Michal J. Besser, Mehdi Khaled, Pierre Close, Ronnie Shapira, Sebastien Apcher, Asaf Madi, Mitchell P. Levesque, Francesca Rapino, Yaron Carmi, Shivang Parikh, Yardena Samuels, Carmit Levy
View2025 HLA
Biological Effects of F(ab’)2 Fragments Generated by Imlifidase From Anti-HLA IgG Antibodies From Transplant Patients
Devriese M, Carelli I, Giraldo L, Pin A, Groshaeny N, Silva SD, Bockermann R, Taupin JL.
View
