Exploring the significance of the CD39-CD73 axis in dual checkpoint inhibition of HNSCC for cancer treatment

• Applicants: Professor Dr. Richard Bauer; Professorin Dr. Anja Kathrin Wege
• Subject Area: Otolaryngology, Phoniatrics and Audiology ; Clinical Immunology and Allergology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 576992023

Immune checkpoint therapies have so far only achieved limited and fragile breakthroughs against head and neck squamous cell carcinoma (HNSCC): a large proportion of patients remain refractory, remissions are rare and often not long-lasting. Our project targets a previously neglected but biologically relevant bottleneck in immune suppression – the CD39/CD73 adenosine pathway – and links it mechanistically to the PD-1 axis and, where appropriate, to LAG-3/TIM-3. The underlying idea is simple and verifiable: if adenosine-driven signals undermine T cell exhaustion and the effect of checkpoint blockades, then dual inhibition can overcome this barrier – provided that we classify patients precisely using valid biomarkers. To this end, we combine patient-derived 3D organoids, humanized patient-derived xenografts (hPDX), and a robust set of biomarkers (enzyme activity and expression of CD39/CD73, soluble checkpoints, functional T-cell readouts). In WP1, we focus on integrated profiling of tumors, blood, and extracellular vesicles to systematically characterize the adenosine microenvironment and checkpoint profiles. In WP2, we identify the most effective synergistic combination compared to mono- and PD-1 standard therapy and transfer this to WP3. In WP3, we will provide preclinical proof of concept in the hPDX system and test a clinically useful patient classification based on CD73 status (positive vs. negative) to validate the predictive significance of CD73. Preliminary work from our collaboration demonstrates the regulated, functionally active CD73/PD-L1 axis in HNSCC, TEX-mediated immunosuppression, and characteristic T-cell exhaustion programs, thus establishing feasibility. Expected outcome: a validated combination strategy against adenosine-mediated resistance, robust response/resistance markers, and a clear stepwise approach for early clinical testing. We address risks associated with tumor heterogeneity or engraftment with adaptive combination therapy, predefined alternatives, and milestones. Why now and why us: The interdisciplinary Regensburg team (Bauer/Wege) combines established cohorts, 3D organoids, and hPDX infrastructure—ideal for moving from mechanism to efficacy to clinical testing in three years.

• DFG Programme: Research Grants