Checkpoint Genes at the Cancer Side of the Immunological Synapse in Bladder Cancer
Paula Dobosz1, Przemysław A Stempor2, Jason Roszik3
1Oncology Institute and Cancer Research Centre, Sheba Medical Centre Hospital, Tel Hashomer, Ramat Gan, Israel.
Abstract:
Immune checkpoint inhibitors have revolutionized cancer therapy, but not all cancers respond to the currently available drugs, and even within cancers considered responsive to such modality, response rates range between 15 and 40%, depending on the cancer type, the line of treatment, and yet unknown clinical/molecular factors. Coordinated expression of checkpoint proteins was shown to occur on T cells, probably allowing fine-tuning of the signal transmitted to the cell. We performed a bioinformatic analysis of the expression of putative checkpoint mRNAs at the cancer side of the immunological synapse from the bladder cancer tumorgenome atlas (TCGA) database. Fifteen mRNAs, corresponding to both coinhibitory and costimulatory checkpoints, were shown to be expressed above a designated threshold. Of these, seven mRNAs were found to be coexpressed: CD277, PD-1L, CD48, CD86, galectin-9, TNFRSF14 (HVEM), and CD40. The expression of 2 of these mRNAs-BTN3A1 (CD277) and TNFRSF14 (HVEM)-was positively correlated with overall survival in the TCGA database. All these seven mRNA share putative binding sites of a few transcription factors (TFs). Of these, the expression of the TF BACH-2 was positively correlated with the expression of checkpoint mRNAs from the network. This suggests a joint transcriptional regulation on the expression of checkpoint mRNAs at the bladder tumor side of the immunological synapse.
Insights
Immune checkpoint inhibitors show limited efficacy. This study identifies seven coexpressed checkpoint mRNAs in bladder cancer, with two linked to better survival, suggesting a regulatory network.
Area of Science:
- Immunology
- Oncology
- Bioinformatics
Background:
- Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but exhibit variable response rates (15-40%).
- Coordinated expression of checkpoint proteins on T cells suggests a regulatory mechanism for immune signaling.
- Understanding these mechanisms is crucial for improving ICI efficacy.
Purpose of the Study:
- To investigate the expression of immune checkpoint-related mRNAs in bladder cancer.
- To identify coexpressed checkpoint molecules at the tumor side of the immunological synapse.
- To explore the correlation between checkpoint mRNA expression, survival, and potential regulatory factors.
Main Methods:
- Bioinformatic analysis of bladder cancer tumor genome atlas (TCGA) database.
- Identification and quantification of putative checkpoint mRNAs.
- Correlation analysis of mRNA expression with overall survival and transcription factors.
Main Results:
- Fifteen checkpoint mRNAs were expressed above a threshold in bladder cancer.
- Seven mRNAs (CD277, PD-1L, CD48, CD86, galectin-9, HVEM, CD40) were coexpressed.
- Expression of BTN3A1 (CD277) and TNFRSF14 (HVEM) correlated positively with overall survival.
- The transcription factor BACH-2 expression correlated with the coexpressed checkpoint mRNAs.
Conclusions:
- A network of coexpressed immune checkpoint mRNAs exists in bladder cancer.
- BTN3A1 and HVEM expression may serve as prognostic biomarkers.
- BACH-2 may jointly regulate these checkpoint mRNAs, offering potential therapeutic targets.
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