Identification of FABP5 as an immunometabolic marker in human hepatocellular carcinoma

Abstract

<jats:sec><jats:title>Background</jats:title><jats:p>Regulating T-cell metabolism is crucial for their anticancer activity. Therefore, understanding the function and metabolism of human tumor-infiltrating T cells is of broad interest and clinical importance.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>CD3<jats:sup>+</jats:sup>CD45<jats:sup>+</jats:sup> T cells were sorted from adjacent area or tumor core of human hepatocellular carcinoma (HCC), then the clusters and heterogeneity of T cells were further interrogated by single-cell transcriptomic profiling. 118 surgical samples from patients with HCC were histologically examined for infiltration of CD8<jats:sup>+</jats:sup> T cells in tumor and adjacent tissue.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Single-cell transcriptomic profiling indicated that several exhausted T-cell (Tex) populations differentially coexisted in the tumor and adjacent tissue. CD137 identifies and enriches Tex with superior effector functions and proliferation capacity. Furthermore, enhanced fatty acid-binding protein 5 (FABP5) expression along with increased mitochondrial oxidative metabolism were evident in these CD137-enriched Tex. Inhibiting FABP5 expression and mitochondrial fatty acid oxidation impaired the anti-apoptosis and proliferation of CD137-enriched Tex. These observations have been verified by generating CD137 CART. Immunohistochemistry staining on the tissue microarray of 118 patients with HCC showed intra-tumoral FABP5 <jats:sup>high</jats:sup> CD8<jats:sup>+</jats:sup> T-cell infiltration was linked to overall and recurrence-free survival.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The tumor microenvironment can impose metabolic restrictions on T-cell function. CD137, a costimulatory molecule highly expressed on some Tex, uses exogenous fatty acids and oxidative metabolism to mediate antitumor immunity. The immunometabolic marker FABP5 should be investigated in larger, longitudinal studies to determine their potential as prognostic biomarkers for HCC.</jats:p></jats:sec>

Lipid-associated macrophages in the tumor-adipose microenvironment facilitate breast cancer progression

“…The oncogenic properties of FFAs transporters have been reported in diverse cancers, including hepatocellular, breast and ovarian cancer. 48–50 However, contrary or contradictory results have been reported, 51 indicating that they have a context-specific role in malignant progression. Consequently, we exclusively sought to determine the functions of FFAs transporters in the TAME.…”

“… 5 , 53–55 Additionally, FFAs carried by these transporters could perturb mitochondrial metabolism to promote naïve T-cell apoptosis, inhibit anti-tumor cytokine secretion and stimulate T cell exhaustion. 48 , 56 Thus, upregulation of these FFAs transporters may accommodate malignant cells to FFAs-enriched TAMEs and formulate an immunosuppressive microenvironment.…”

Intracellular Lipid Accumulation Drives the Differentiation of Decidual Polymorphonuclear Myeloid-Derived Suppressor Cells via Arachidonic Acid Metabolism

“…It has been reported that FABP5 can reprogram lipid metabolism and promote progression and metastasis in tumors ( 74 – 76 ). Furthermore, FABP5 has been shown to act as a critical regulator of immune cells in microenvironments via lipid metabolism, including the protection of tissue-resident memory T cells ( 77 ), the induction of suppressive T regulatory cells ( 67 , 78 ), the maintenance of T lymphocyte homeostasis ( 79 ), the production of tolerogenic plasmacytoid dendritic cells ( 78 ), and macrophage polarization, and has also been identified as a prognostic immune-metabolic marker ( 80 , 81 ). Similarly, we identified the immunomodulatory effect of FABP5 during the differentiation of decidual PMN-MDSCs.…”

Cancer as a Metabolic Disorder

“…FABP5 is the most characterized FABP isoform in cancers. Increased FABP5 expression has been reported in hepatocellular carcinoma, cholangiocarcinoma, and liver, pancreatic, cervical, and breast cancers [96][97][98][99][100]. FABPs are rapidly emerging as essential proteins in fatty acid transport and metabolism in cancer cells.…”