Dissecting the function of LAG-3 in T follicular helper cells in cancer and cancer immunotherapy

• Applicant: Professor Dr. Dirk Baumjohann
• Subject Area: Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536814295

T follicular helper (Tfh) cells provide essential help to B cells for potent antibody responses. While the critical function of these CD4+ T cells in infection and vaccination is well established, their involvement in cancer is just emerging. In various solid cancer types, the presence of Tfh cells frequently coincides with a better prognosis. Nevertheless, Tfh cells may also exacerbate immune-related adverse events (irAEs), e.g. development of secondary autoimmunity, during immune checkpoint blockade (ICB). Similar to PD-1, LAG-3 is an inhibitory receptor expressed by T cells and Tfh cells, with the first anti-LAG-3 ICB combination therapy with anti-PD-1 recently approved by the FDA for patients with unresectable or metastatic melanoma. However, LAG-3’s function in Tfh cells and how LAG-3 ICB impacts Tfh cells remains unknown. Therefore, we here propose to combine fate-mapping, induced conditional deletion of Tfh cell-relevant genes, LAG-3 ICB, and LAG-3 knockouts to dissect the function of LAG-3 in Tfh cells in vivo in the context of an established solid tumor model as well as in cancer immunotherapy. The results of these studies should provide a better understanding of the underlying processes and mechanisms that could then inform improved treatment and personalized medicine approaches.

• DFG Programme: Research Grants