Immune
microenvironment and
Immunotherapy
The “Immune Microenvironment and Immunotherapy” team is composed of scientists and clinicians with complementary expertise in the fields of tumor immunology and immunotherapy, as well as in AI-assisted imaging and bioinformatics—including single-cell and spatial transcriptomic analyses.
Team members are also deeply involved in university teaching and regularly collaborate with partners in hospitals and the pharmaceutical industry at both the national and international levels.
Unlike regulatory T cells (Tregs), the presence of Tertiary Lymphoid Structures (TLS) in the tumors of cancer patients—first described by the team—has a favorable prognostic value. Our research projects therefore focus on the relationships between TLS and the tumor microenvironment (TME) in patients with various cancers or at risk of developing cancer, as well as on the manipulation of TLS or regulatory T cells in syngeneic or humanized models, with the aim of developing new therapeutic strategies applicable to humans.
Alveoli, bronchus and artery in murin lung
0Colocalization of blood vessels and sympathetic nerve fibers in the ear of mouse
Germinal center with CD20+ B cells (green) and CD21+ follicular dendritic cells (orange) of a
tertiary lymphoid structure associated with human lung tumor
T cell (green and orange) and B cell (blue) segregation within tertiary lymphoid structures in human lung tumor
Development of tumor- associated tertiary lymphoid structures in lung tumor model
The team members
Our research focus on 3 axes
- Tertiary lymphoid structure
- Human and murine tumor immunology
- T and B cell immunity
- Therapeutic manipulation of TLS
- Regulatory T cell
- Lung and head and neck carcinomas
- Pain
- Glioblastoma
- Onco-Neuro-Immunology
- Lichen plan
1. Characterization of the molecules and cells that regulate the immune function of TLS
Numerous studies by the team have shown that the presence of TLS in tumors correlates with Th1 polarization, cytotoxic activity of lymphocytes, and improved patient survival. Furthermore, B lymphocytes in TLS correlate with the presence of plasma cells secreting antibodies directed against tumor antigens.
The molecular characteristics of the tumor and the functionality of intratumoral T and B cells are being studied with the aim of identifying new cellular interactions that underlie effective antitumor responses.
By combining cellular and molecular approaches in mouse models and using human tumor biopsies, our objectives are: i) to identify the cell population(s) involved in the development of TLS under various inflammatory conditions; ii) to evaluate the role of neovascularization and nerve fibers in the formation and maintenance of TLS; and iii) to identify soluble and membrane-bound molecules involved in the development of TLS.
2. ChDevelopment of Immunotherapies Based on Targeting TLS
The ability to generate and maintain functional TLS in the TME would represent a promising new approach to immunotherapy for controlling tumor growth and inducing powerful, long-lasting immune surveillance against cancer cells. We are currently developing antibody (Ab)-based fusion molecules to trigger and/or enhance the presence of functional TLS in the TME. Their ability to recruit and stimulate tissue-lymphoma-inducer (LTi)-like cells is being studied in various preclinical models.
3. The Role of Regulatory T Cells in the Cancer-Induced Immune Response
Unlike TLS, Tregs are generally associated with a poor prognosis in cancer patients. A better understanding of the signals that cause Tregs to inhibit the immune response against cancer would lead to more effective therapies. Recent findings from the team point to a role for Tregs in regulating nociception during tumor development. We combine syngeneic or humanized mouse models, human bioinformatics analyses, and in vitro cultures to discover and validate molecules that would allow us to target Tregs in order to both prevent their immunosuppressive effects and enhance their analgesic effects.
The opportunities
- Identification of molecules that trigger TLS neogenesis and their antitumor properties.
- Combination therapies based on proprietary antibodies that profoundly reshape the tumor microenvironment.
- Optimization of anti-cancer immunotherapies through the development of new therapeutic vaccines and new immunomodulatory molecules.
- Development of bioinformatics and artificial intelligence analysis tools.
Publications
The Sunrise of Tertiary Lymphoid Structures in Cancer. Immunol Rev. 2025 Jul;332(1):e70046. doi: 10.1111/imr.70046.PMID: 40591148
Tertiary Lymphoid Structures – Dieu-Nosjean, M.-C. (Éd.). (2025). Tertiary Lymphoid Structures : Methods and Protocols (Vol. 2864). Springer US. https://doi.org/10.1007/978-1-0716-4184-2
Inhibition of A2AR alleviates adenosine-mediated suppression of plasma cell differentiation. Front Immunol. 2025 Dec 15;16:1702402. doi: 10.3389/fimmu.2025.1702402. eCollection 2025.PMID: 41472728
Regulatory T Cells Poise the Myeloid Landscape after Chemotherapy in Lung Tumors. Cancer Immunol Res. 2025 Oct 1;13(10):1561-1575. doi: 10.1158/2326-6066.CIR-25-0103.PMID: 40601834
The prognostic significance of tertiary lymphoid structures in oral squamous cell carcinomas: a systematic review. Front Oral Health. 2025 Jan 22;5:1524313. doi: 10.3389/froh.2024.1524313. eCollection 2024.PMID: 39911478
Tertiary Lymphoid Structures Are Associated with Enhanced Macrophage Activation and Immune Checkpoint Expression and Predict Outcome in Cervical Cancer. Cancer Immunol Res. 2025 May 2;13(5):712-728. doi: 10.1158/2326-6066.CIR-24-0979.PMID: 39888676
Has the Holy Grail of humanized mice been found ?]. Med Sci (Paris). 2025 Apr;41(4):308-309. doi: 10.1051/medsci/2025050. Epub 2025 Apr 28.PMID: 40294289
[Enkephalins produced by regulatory T lymphocytes modulate pain in mice]. Med Sci (Paris). 2025 Feb;41(2):127-129. doi: 10.1051/medsci/2025006. Epub 2025 Mar 3.PMID: 40028948
Absence of sympathetic innervation hampers the generation of tertiary lymphoid structures upon acute lung inflammation. Sci Rep. 2024 May 23;14(1):11749. doi: 10.1038/s41598-024-62673-0.
Enkephalin-mediated modulation of basal somatic sensitivity by regulatory T cells in mice. N Aubert, M Purcarea, M Fornier, L Cagnet, M Naturel, A Casrouge, G Dietrich, M-C Dieu-Nosjean, G Marodon. eLife. 2024 February 1.
[The Nobel Prize in Physiology or Medicine 2023: Katalin Karikó and Drew Weissman – A vaccine revolution driven by fundamental research in immunology and molecular biology]. Med Sci (Paris). 2024 Feb;40(2):186-191. doi: 10.1051/medsci/2024002. Epub 2024 Feb 27.
SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma. Blood. 2022 Feb 24;139(8):1160-1176. doi: 10.1182/blood.2021012448. PMID: 35201323
BMFPs, a versatile therapeutic tool for redirecting a preexisting Epstein-Barr virus antibody response toward defined target cells. Sci Adv. 2022 Feb 11;8(6):eabl4363. doi: 10.1126/sciadv.abl4363. Epub 2022 Feb 11. PMID: 35148183 Free PMC article.