Single-cell RNA-sequencing of BCG naïve and recurrent non-muscle invasive bladder cancer reveals a CD6/ALCAM-mediated immune-suppressive pathway
Bacillus Calmette-Guérin (BCG) is the mainstay of treatment for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC), yet recurrence rates remain high. To improve the efficacy of BCG, a better understanding of the immune landscape underlying BCG resistance is critical. Here, we performed single-cell RNA-sequencing (scRNA-seq) and whole-exome sequencing on tumors from NMIBC patients before and after BCG treatment. Our analysis revealed a marked increase in CD6/ALCAM interactions between T cells and urothelial cells in BCG recurrent tumors. CD6-high T cells were enriched in recurrent tumors and exhibited downregulation of activation-related genes, indicative of functional impairment. These observations were supported by analysis of an independent BCG-treated NMIBC cohort, in which CD6/ALCAM signaling was correlated with shorter recurrence-free survival (p = 0.00059). Our findings reveal a previously unrecognized association between CD6/ALCAM signaling and BCG resistance in NMIBC patients and highlight this pathway as a potential therapeutic target to enhance response to BCG.
Authors
- Gad A. Getz (ORCID: https://orcid.org/0000-0002-0936-0753)
- Tyler Joseph Alban (ORCID: https://orcid.org/0000-0002-3261-140X)
- Angela H. Ting (ORCID: https://orcid.org/0000-0002-3214-3968)
- Hong Qiu (ORCID: https://orcid.org/0000-0001-5239-904X)
- Pierre-Emmanuel Desprez (ORCID: https://orcid.org/0000-0002-6628-2210)
- Emily E. Fink (ORCID: https://orcid.org/0000-0003-2738-5732)
- Booki Min
- Nima Almassi (ORCID: https://orcid.org/0000-0002-6307-9268)
- Arvind Ravi
- Ivan Jurić (ORCID: https://orcid.org/0000-0002-1076-6320)
- Mark Holton
- Byron Lee (ORCID: https://orcid.org/0000-0002-8755-9688)
- Vladimir Makarov (ORCID: https://orcid.org/0000-0001-9622-1550)
- Timothy A. Chan
Institutions
- Broad Institute (US)
- Northwestern University (US)
- Cleveland Clinic (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Charles River Laboratories (Netherlands) (NL)
- Centre Hospitalier Universitaire de Lille (FR)
- Cleveland Clinic Lerner College of Medicine (US)
- Charles River Laboratories (United States) (US)
- Center for Cancer Research (US)
- Hôpital Claude Huriez (FR)
- Case Western Reserve University (US)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1038/s41698-025-01093-3
- Citations
- 1
- Primary Topic
- Bladder and Urothelial Cancer Treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.01
Funders
- Massachusetts General Hospital
- Cleveland Clinic
- National Institutes of Health
- National Cancer Institute