Specific immune patterns in metastases determine the success of therapy
Important step towards a more precise, biomarker-guided therapy for metastatic renal cell carcinoma
Today, metastatic renal cell carcinoma is increasingly being treated with immunotherapies. But which patients actually benefit from this treatment? This question could not be answered reliably until now. Researchers at the University Hospitals of Würzburg and Erlangen have now made a decisive discovery with the help of high-resolution spatial transcriptomics technologies: It is not the characteristics of the original kidney tumor, but specific immune patterns in the metastases that are decisive for the success of the therapy. The results have now been published in the renowned Journal for ImmunoTherapy of Cancerpublished.
Renal cell carcinoma is the most common form of kidney cancer in adults. It develops in the cells of the renal tubules and can spread to other organs such as the lungs, liver or bones in advanced stages. Thanks to modern immunotherapies, the prognosis has improved significantly - many patients can now live with the disease for several years. However, one in five patients does not respond at all to first-line treatment with immune checkpoint inhibitors, and in a further 20 percent the cancer becomes active again within the first year.
"The selection of first-line therapy is currently mainly based on a clinical risk assessment that takes into account the course of the disease, laboratory values and general condition," explains Dr. Charis Kalogirou, Managing Senior Physician at the Clinic and Polyclinic for Urology and Pediatric Urology at the University Hospital of Würzburg (UKW). "However, there is increasing evidence that the response to treatment depends more on the nature of the tumor and the spatial and cellular complexity of the tumor microenvironment than on the clinical risk."
Maps of the tumor reveal hidden immune patterns
To get to the bottom of this puzzle, Kalogirou and his team examined tissue samples from twelve patients with metastatic renal cell carcinoma who were treated at the Würzburg Urology Department. By using high-resolution spatial transcriptomics, the researchers were able to create detailed "maps" of the tumor and its metastases. These show which and how many immune system defence cells are present in the tumor environment, how active they are and how close they are to the cancer cells. They have now published their results in the Journal for ImmunoTherapy of Cancer.
"We found that there is not just one immune state in the kidney tumor, but different local environments with their own profile," reports Charis Kalogirou, first author of the study. Even tumors that were considered the same according to conventional classification showed considerable differences between individual patients and even within a tumor. Particularly surprising: primary tumors and metastases differed significantly in their cellular composition and spatial arrangement.
"Almost two years ago, we were able to establish similar correlations for urothelial carcinoma - and now also for renal cell carcinoma," adds Dr. Markus Eckstein, Managing Senior Physician at the Institute of Pathology of the University Hospital Erlangen and last author of the study. "In particular, the analysis of the immune microenvironment of the metastases is highly relevant for the response to immunotherapies and could significantly improve therapy selection in the future."
Favorable immune niches predict therapy success
The key discovery: In the metastases, the researchers were able to identify so-called "immune niches" - areas in the tumor tissue in which macrophages and CD8+ T cells interact intensively with each other through chemokine signals. "Patients with these niches in their metastases responded significantly better to immunotherapy," explains Kalogirou. "In the original kidney tumors, however, this favorable niche hardly ever occurred."
A gene signature derived from these findings was also able to reliably predict the response to therapy in independent international studies involving more than 1,000 patients. In areas that remained resistant to the therapy, however, genes that represent a suppressed immune response dominated. In addition to the type of cells, their spatial arrangement was also decisive - i.e. how close the immune cells are to the tumor cells and which genes they activate.
More precise therapy selection within reach
"So it is not enough to know that there are immune cells in the tumor. It is also crucial to know where they are and how they work," summarizes Charis Kalogirou. The analysis of metastasis biopsies could help doctors in future to better predict whether their patients will benefit from immunotherapy. If not, patients would be spared less effective treatments or treatments with many side effects.
"This is an important step towards more precise, biomarker-guided cancer therapy," Kalogirou is convinced. The integration of spatial analyses of the tumour microenvironment in future studies could significantly advance personalized immunotherapy for metastatic renal cell carcinoma.
Publication:
Kalogirou C, Krebs M, Kunz AS, Hahn O, Kübler H, Schwinger M, et al. Spatial transcriptomic profiling of metastatic renal cell carcinoma identifies chemokine-driven macrophage and CD8+ T-cell interactions predictive of immunotherapy response. Journal for ImmunoTherapy of Cancer. 2025;13:e012991. https://doi.org/10.1136/jitc-2025-012991
