Low-branching vessel architecture shapes immune cell niches and predicts immune responses in renal cancer
Toma, M. I.; Li, Y.; Kehl, M.; Kempchen, T. N.; Esser, L.; Baschun, K.; Leonardelli, S.; Pinetz, T.; Turiello, R.; Yong, M. C. R.; Pelusi, N.; Altamirano-Escobedo, G.; Bayro-Corrochano, E.; Kadzik, S.; Eckstein, M.; Flatz, L.; Hörst, F.; Kleesiek, J.; Saal, J.; Kristiansen, G.; Ritter, M.; Ellinger, J.; Grünwald, V.; Klümper, N.; Effland, A.; Hölzel, M.
Show abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by marked histological heterogeneity, encompassing its vasculature. Here, we introduce PropSegNet, a learning-based algorithm that segments and classifies three distinct vascular patterns in CD31-stained tissue sections. Integrating transcriptomic features, our work identifies a trajectory from high- to low-branching vessel architecture that co-evolves with the loss of proximal tubular cell traits in tumor cells. Furthermore, low-branching vessels form niches enriched with T cells and antigen-presenting cells. Mechanistically, air-liquid-interface cultures of patient-derived tumor fragments confirm that low-branching vessel features associate with T cell infiltration resulting in reduced viability under IL-2 rich conditions. Post-hoc transcriptomic analyses from two phase III clinical trials demonstrate that patients with tumors exhibiting an inflamed, low-branching vascular phenotype benefit most from the addition of immune checkpoint inhibition to anti-angiogenic treatment. These findings provide a rationale for prospective evaluation of vascular patterns and vessel-immune cell niches as potential biomarkers in ccRCC.
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