ACSM6 overexpression indicates a non-inflammatory tumor microenvironment and predicts treatment response in bladder cancer: results from multiple real-world cohorts

Zhiwei Li; Yiyan Yao; Tiezheng Qi; Zuowei Wu; Dingshan Deng; Bolong Liu

doi:10.3389/fphar.2023.1222512

ACSM6 overexpression indicates a non-inflammatory tumor microenvironment and predicts treatment response in bladder cancer: results from multiple real-world cohorts

Front Pharmacol. 2023 Jun 22:14:1222512. doi: 10.3389/fphar.2023.1222512. eCollection 2023.

Authors

Zhiwei Li¹, Yiyan Yao², Tiezheng Qi², Zuowei Wu³, Dingshan Deng^{4

5}, Bolong Liu^{4

5

6}

Affiliations

¹ The Second Affiliated Hospital, Department of Urology, Hengyang Medical School, Unversity of South China, Hengyang, Hunan, China.
² Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
³ Department of Interventional Radiology, Third Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Urology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁵ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁶ The First Affiliated Hospital, Department of Andrology, Hengyang Medical School, University of South China, Hengyang, China.

Abstract

Background: ACSMs play critical roles in lipid metabolism; however, their immunological function within the tumor microenvironment (TME) remains unclear, especially that of ACSM6. In this study, we investigate the latent effect of ACSM6 on bladder cancer (BLCA). Methods: Several real-world cohorts, including the Xiangya (in-house), The Cancer Genome Atlas (TCGA-BLCA), and IMvigor210 cohorts, with TCGA-BLCA cohort serving as the discovery cohort were compared. We investigated the potential immunological effects of ACSM6 in regulating the BLCA tumor microenvironment by analyzing its correlation with immunomodulators, anti-cancer immune cycles, immune checkpoints, tumor-infiltrating immune cells, and the T-cell inflamed score (TIS). Additionally, we assessed the precision of ACSM6 in predicting BLCA molecular subtypes and responses to several treatments using ROC analysis. To ensure the robustness of our findings, all results were confirmed in two independent external cohorts: the IMvigor210 and Xiangya cohorts. Results: ACSM6 expression was markedly upregulated in BLCA. Our analysis suggests that ACSM6 might have significant impact to promote the formation of a non-inflamed tumor microenvironment because of its negative correlation with immunomodulators, anticancer immune cycles, immune checkpoints, tumor-infiltrating immune cells, and the T-cell inflamed score (TIS). Additionally, high ACSM6 expression levels in BLCA may predict the luminal subtype, which is typically associated with resistance to chemotherapy, neoadjuvant chemotherapy, and radiotherapy. These findings were consistent across both the IMvigor210 and Xiangya cohorts. Conclusion: ACSM6 has the potential to serve as a valuable predictor of the tumor microenvironment phenotypes and treatment outcomes in BLCA, thereby contributing to more precise treatment.

Keywords: ACSM6; bladder cancer; chemothearpy bladder cancer; chemotherapy; immunotherapy; tumor microenvironment.