Unraveling the dysfunctions of the CD40L:CD40 signaling axis in patients with renal cell carcinoma to develop advanced therapeutic strategies

• Applicant: Dr. Marco Frentsch
• Subject Area: Nephrology ; Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 546141032

Immunotherapies can achieve remarkable success in tumor patients. However, a large proportion of patients fail to achieve long-lasting treatment success, and new therapies are still urgently needed. In preliminary work, we demonstrated that expression of CD40L on activated CD8+ T cells is essential for in vivo tumor immunity in CD40+ tumors. Many human tumor entities express CD40 and T-cell-mediated cross-linking of CD40 by CD40L can induce apoptosis in cancer cells, whereas binding of αCD40 antibodies solely is often not sufficient for killing cancer cells and is more likely to cause undesired systemic activation of non-malignant CD40+ cells in vivo. To understand why the CD40L:CD40 signaling axis fails for tumor control in progressive disease, we aim to characterize CD40L+ tumor-infiltrating T cells and determine their antigen specificity. We further plan to determine the heterogeneity of sensitivity to CD40- The goal is to decipher the dysregulations of the CD40L-CD40 signaling axis (inhibition/attenuation of signaling by the cancer cell, lack of additional/essential signals for tumor immune surveillance) that result in impairments of anti-tumor activity and, based on these findings, to develop effective and safe therapeutic strategies for renal cell carcinoma and presumably for CD40+ expressing tumors in general.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Il-Kang Na