Abstract
Purpose Bladder cancer (BLCA) is a heterogeneous tumor type. Only one third of muscle-invasive (MIBC) patients respond to immune checkpoint inhibitors (ICIs). Reliable resistance markers are needed to guide clinical decisions. We investigated the nerve growth factor receptor (NGFR) in BLCA and analyzed its correlation with disease progression and response to immunotherapy.
Experimental Design We analyzed NGFR expression in BLCA cell lines, organoids, mouse models and patient samples. The cohorts used were The Cancer Genome Atlas (TCGA), enriched in muscle-invasive bladder cancer (MIBC) (n=407); IMvigor210, representing MIBC patients treated with ICIs (n=348); and UROMOL2, as a non-muscle-invasive bladder cancer (NMIBC)-specific cohort (n=535). IMvigor010 was also included (n=728). Patients were stratified by NGFR expression quartiles. We analyzed survival and tumor subtypes and performed stromal deconvolution and functional profiling. We assessed stemness- and invasion-related features in SCaBER cells.
Results
NGFR marks a basal tumor cell subcluster and is independently associated with poor prognosis in TCGA and IMvigor210. NGFR-high tumors show stromal content enriched in cancer-associated fibroblasts, lower neoantigen burden, higher CD8+ T effector signature together with an immune-excluded phenotype, and a CAF-specific TGFβ signature. In the immunotherapy-treated cohort, high NGFR expression was also associated with poorer outcome. Functionally, NGFR appears to promote a stem-like/pro-invasive program in BLCA cells.
Conclusions
NGFR identifies a basal-like BLCA subpopulation linked to poor survival, while its association with immunotherapy response requires further validation. In addition, our in vitro analyses support a role of NGFR in stem-like and invasive traits, highlighting its relevance as a biomarker in BLCA.
Competing Interest Statement
Nuria Malats and Francisco X Real declare Research funding from Janssen Markus Eckstein reports advisory roles for Janssen, BicycleTX, AstraZeneca, MSD, Cepheid, Diaceutics, and GenomicHealth; personal fees and travel costs from Janssen, AstraZeneca, MSD, Cepheid, Diaceutics, and GenomicHealth, BicycleTX; research support from Janssen, AstraZeneca, Cepheid, Gilead, BicycleTX, QuIP GmbH and STRATIFYER; speaker honoraria from Janssen, AstraZeneca, MSD, Diaceutics, Roche, Zytomed Systems and Astellas; and part-time employment at Diaceutics, BicycleTX (clinical advisory board). Stock ownership: BicycleTX. The rest of the authors declare no competing interests.