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SLC4A4 Moulds the Inflammatory Tumor Microenvironment and Predicts Therapeutic Expectations in Colorectal Cancer


Dan Xiang, Huiyu Li, Jun Pan and Yitian Chen*   Pages 1 - 18 ( 18 )


Background: Colorectal cancer (CRC) cases with advanced or distal metastases experience a survival rate of less than 20%, with the lack of spectral therapeutic targets and prognostic markers posing a significant challenge for CRC treatment. SLC4A4 may be a CRC-targeted therapy for which there is currently inadequate evidence.

Aim: In this report, we performed a comprehensive analysis of data on colorectal cancer (CRC) to elucidate the association among Solute Carrier Family 4 Member 4 (SLC4A4) and the abundance of immunological features and immune cell infiltration in CRC and to explore the impact of SLC4A4 on the CRC tumor microenvironment.

Objective: The objective of this study was to systematically reveal the characteristics of the tumor microenvironment created by SLC4A4.

Methods: We downloaded RNA sequencing files from the Cancer Genome Atlas (TCGA- COADREAD). The correlations of SLC4A4 with immune-related characteristics were analyzed. A Limma package was applied for selecting SLC4A4/immunity-related differentially expressed genes (DEGs). An assessment system for predicting CRC prognosis was constructed based on univariate COX and multivariate COX analyses. A nomogram was also designed to assess the survival risk status of CRC. Besides, we evaluated the potential association of SLC4A4 to immunotherapy through TIDE analysis.

Results: We found that SLC4A4 expression was positively correlated with immune checkpoint expression (PD-L1). SLC4A4 promoted the infiltration of CD8 T cells, dendritic cells, macrophages, NK cells, and Th1 cells in CRC, shaping the inflammatory tumor microenvironment. Up-regulated SLC4A4 might improve drug response to anti- FGFR3 therapy, anti-PPARG therapy, nivolumab, and ipilimumab in CRC patients, and down-regulated SLC4A4 might promote drug response to anti-EGFR therapy and Aflibercept drug response. The constructed RiskScore model showed excellent predictive effect and robustness. RiskScore presented a trend of negative correlation with SLC4A4, which was consistent with the trend of the effect of SLC4A4 on CRC survival. TIDE analysis further disclosed that high-risk groups with high levels of SLC4A4 were possible for immune escape. Finally, the constructed nomogram also showed potential clinical value.

Conclusion: Overall, upregulation of SLC4A4 expression promoted an inflammatory tumor microenvironment in CRC, and RiskScore predicted therapeutic expectancy. SLC4A4 could be a potentially clinically valuable target for CRC therapy.


Colorectal cancer, SLC4A4, prognosis, immunotherapy, immunogenicity.


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