Y Chromosome Loss in Bladder Cancer - Expert Commentary
The investigators first analyzed transcriptomic data from 300 males with muscle-invasive bladder cancer (MIBC) using The Cancer Genome Atlas (TCGA). The samples were divided into high and low Y chromosome signatures based on expression levels of Y chromosome genes. Patients in the Ylow group exhibited lower survival than those in the Yhigh group (p = 0.024). Moreover, decreased expression of four Y chromosome genes alone was linked to poor prognosis (KDM5D, UTY, TBL1Y, and ZFY). Next, the researchers used the MB49 mouse cell line, which exhibits spontaneous LOY, to isolate Y+ and Y- cells. There was no difference in proliferation of the two populations in 2D or 3D culture. However, wild-type mice injected with Y- cells exhibited a twofold increase in tumor growth rate relative to those injected with Y+ cells.
Interestingly, both cell types grew at the same rate in immunocompromised mice (Rag2-/-Il2rg-/-), indicating a link to immunity. CRISPR-based knockout of the Y chromosome genes led to similar effects. Knockdown and overexpression experiments with two Y chromosome genes (Uty and Kdm5d) revealed their involvement in impaired anti-tumor immunity in Y- tumors. This was found to be directly linked to T cells as differential growth was eliminated in mice lacking T cell receptors. The team then profiled the transcriptomic data from Y+ and Y- MB49 tumors in wild-type mice, identifying 958 differentially expressed genes (DEG). Y+ tumors exhibit enhanced immune response compared to Y- tumors. Upon sorting cells using flow cytometry, there was a higher proportion of PD-L1-positive immune cells and higher PD-L1 expression in Y- tumors. This was also validated in an independent MIBC patient dataset and increased expression of markers of exhausted T cells. Treatment with anti-PD-1 antibodies improved response in Y- tumors compared to Y+ tumors. This was consistent with results from the Imvigor210 clinical trial in patients with bladder cancer, in which Ylow patients had better outcomes after anti-PD-L1 treatment. Expression of UTY and KDM5D also allowed for risk stratification of patients by the outcome. Ylow tumors also exhibited higher expression of markers of DNA damage repair pathways, reflecting higher genomic instability and increased tumor neoantigen burden.
The findings from this important study highlight the potential clinical benefit of understanding the biology of LOY. Furthermore, LOY is a potential biomarker for identifying patients with bladder cancer who are likely to benefit from immune checkpoint blockade. In addition, follow-up studies may evaluate the feasibility and efficacy of inhibiting UTY and KDM5D in the context of LOY.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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