Abstract
ObjectiveThis study aimed to explore the role of ACSL4 in CD8+ T cell tumor infiltration and outcomes of bladder cancer (BLCA) patients after immunotherapy.MethodsThe correlation between ACSL4 expression and tumor infiltration of immune cells was analyzed using the Tumor Immune Estimation Resource database. The prognostic significance of ACSL4 in BLCA was analyzed using Kaplan–Meier curves. Immunohistochemistry was used to detect CD8+ T cell infiltration in tumors with high and low ACSL4 expression obtained from patients at the Fudan University Shanghai Cancer Center. The relationships between immune checkpoint genes and immune response were analyzed using The Cancer Genome Atlas and IMvigor 210 cohorts. The molecular functions, cellular components, and biological processes involving ACSL4 were explored using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment pathway analyses.ResultsThe expression level of ACSL4 was significantly correlated with the infiltration of CD8+ T cells in BLCA tumors (r = 0.192, P = 2.22e-04). Elevated ACSL4 was associated with suppressed tumor progression and better outcomes for BLCA patients. The higher expression level of ACSL4 predicted better immunotherapeutic responses and was associated with higher expression levels of core immune checkpoint genes, including CD274, CTLA4, PDCD1, and LAG3, compared with the low ACSL4 expression group.ConclusionThis study demonstrated for the first time that elevated ACSL4 correlated significantly with CD8+ T cell infiltration and contributed to better immunotherapeutic responses in BLCA patients. Furthermore, ACSL4 serves as a novel biomarker for predicting patient outcomes after immunotherapeutic treatments, which may improve the development of individualized immunotherapy for BLCA.
Highlights
Bladder cancer (BLCA) is the ninth most common malignant tumor worldwide, with approximately 81,400 new cases and 17,980 deaths reported in the United States in the year 2020 [1]
The expression level of Acyl-CoA synthetase long-chain family member 4 (ACSL4) was positively correlated with the expression of CD8A (R = 0.174, P = 4.1e-04) and CD8B (R = 0.267, P = 4.84e-08) marker genes, further confirming a role for ACSL4 in CD8+ T cell infiltration (Figure 1B)
The results showed that ACSL4 expression was significantly higher in tumor in situ (TIS) and non-muscle-invasive BLCA (NMIBC) compared with muscle-invasive BLCA (MIBC), which suggested that ACSL4 may play a role in preventing BLCA invasion by facilitating immune cell infiltration (Figure 2B)
Summary
Bladder cancer (BLCA) is the ninth most common malignant tumor worldwide, with approximately 81,400 new cases and 17,980 deaths reported in the United States in the year 2020 [1]. According to the latest reports, the median overall survival of patients with relapsed or refractory BLCA after cisplatin treatment was only 14–15 months [3]. The United States Food and Drug Administration has approved five PD-1/PD-L1 inhibitors as first- or second-line treatments for patients with advanced BLCA [4]. Among patients with advanced BLCA, the overall response rates for ICI treatments are 13–24% [5, 6]. Because the majority of advanced BLCA patients do not benefit from these immunotherapeutic agents, it is important to identify new biomarkers for predicting treatment response
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