Fatty Acid Metabolism Shapes Immune Function and PI3K Inhibitor Sensitivity in Chronic Lymphocytic Leukemia

Introduction: Chronic lymphocytic leukemia (CLL) progression might be subject to fatty acid metabolic reprogramming. However, precisely how fatty acid metabolism (FAM) is involved in CLL pathogenesis is elusive. The present study elucidated the transcriptomic signatures of FAM, which indicate differences in prognosis and immune function, and investigated the metabolism-dependent sensitivity to PI3K inhibitor in CLL.

Methods: The prognostic model FAM-Score based on fatty acid metabolic genes was constructed in the training cohort of 487 CLL patients by Cox-LASSO regression analyses and validated in the independent cohort of 195 CLL patients. The samples were analyzed using the ssGSEA and CIBERSORT algorithms to define the immunometabolism landscape of CLL patients. Moreover, the reciprocal molecules of the FAM-related genes were identified from single-cell RNA sequencing analysis of CLL patients. Functional enrichment analysis was performed using the Gene Ontology (GO) database. CCK-8 was used to detect cell viability treated with PI3K inhibitor idelalisib following inhibition of fatty acid oxidation.

Results: The fatty acid metabolic genes LPL, SOCS3, and CNR1 with independent prognostic significance were selected from 864 differentially expressed genes to construct the FAM-Score. The ROC analysis showed better specificity and sensitivity of FAM-Score (AUC = 0.738, p < 0.001) than Binet stage (AUC = 0.527, p = 0.487). The Kaplan-Meier curves suggested a significant association between high-risk subgroup and undesirable overall survival in CLL patients (p < 0.001). To further investigate the role of the FAM-Score in the CLL immune microenvironment, the abundance of immune cells between the two subgroups was quantified for comparison. The results showed significant differences in T cells, NK cells, and macrophages, suggesting the impact of FAM in CLL immunophenotype. Consistently, the expression of LPL, SOCS3, and CNR1 showed evident immune cell subset specificity at the single-cell level in CLL patients. To investigate the mechanism of FAM-induced differences in CLL immunophenotype, the reciprocal molecules of the key genes were identified. The results of functional analysis demonstrated that the interacting genes are enriched in the immune cell activation pathway and its regulatory pathways. Moreover, the fatty acid oxidation pathway, in which the differentially expressed genes of patients with higher FAM-Score were notably enriched, was significantly more active in CLL patients than in healthy controls at the single-cell level. Therefore, CLL cells were treated with the fatty acid oxidation inhibitor perhexiline, which demonstrated that the inhibition of fatty acid oxidation impeded the survival of CLL cells and enhanced their sensitivity to PI3K inhibitor idelalisib.

Conclusions: The present study identified a robust clinical prognostic score based on fatty acid metabolic genes and revealed the immunophenotypic differences in CLL related to FAM-Score. Inhibiting fatty acid oxidation in CLL cells enhances the therapeutic efficacy of the PI3K inhibitor and suppresses cell proliferation activity. Although the specific mechanisms of FAM underlying CLL progression are not fully clarified, FAM pathways represent a promising avenue for amplifying the therapeutic strategies against CLL.

No relevant conflicts of interest to declare.