Critical Determinants of Response to Immunotherapy in Non-clear Cell RCC Entities

• Applicants: Professorin Dr. Barbara T. Grünwald; Professor Dr. Arndt Hartmann; Professorin Dr. Barbara Seliger
• Subject Area: Pathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568914561

Non-clear cell renal cell carcinoma (nccRCC) is a highly aggressive cancer with various subtypes, each having distinct molecular and histologic characteristics. It shows considerable spatial heterogeneity in mutational profiles, gene expression, and immune responses, which makes it challenging to treat with immune checkpoint inhibitors (ICIs). This spatial variation contributes to resistance to treatment and failure to respond to therapies. However, the mechanisms behind these variations and how they influence ICI effectiveness remain poorly understood. The SUNNIFORECAST trial, a large study on nccRCC, compared the effectiveness of nivolumab and ipilimumab (two ICIs) to standard treatments in patients with advanced, treatment-naive nccRCC. While the combination therapy improved overall survival and objective response rates, it did not significantly affect progression-free survival, and many patients still failed to benefit. These results highlight the complexity of ICI response in nccRCC and the urgent need to understand the underlying molecular and immune mechanisms and to identify reliable biomarkers for predicting ICI response or resistance. To address this, the CRITERIA project, a multidisciplinary study, will use clinical samples and data from the SUNNIFORECAST trial to explore the heterogeneous tumor microenvironment (TME) of nccRCC and to decipher the key factors driving immune responses. The project will employ a multi-omics approach combining histology, genetic, epigenetic, and immune profiling to understand the tumor's complex biology and immunology. By integrating advanced spatial technologies, single-cell analyses, and AI, CRITERIA aims to map tumor-immune-stromal interactions in unprecedented detail. The ultimate goal of the CRITERIA project is to identify biomarkers that can predict non- responders and responders to ICI. The study is designed to translate these molecular and immunological findings into clinically actionable decision-support tools, improving treatment selection and overcoming the limitations of current approaches. This research aims to transform the management of nccRCC by enabling personalized, biomarker-driven treatment strategies, addressing a significant unmet need in a disease that currently lacks molecularly tailored therapies.

• DFG Programme: Research Grants
• International Connection: France
• Co-Investigator: Professor Dr. Lothar Bergmann
• Cooperation Partner: Professor Dr. Gabriel Malouf