T Cell Lipid Metabolism and Function by FABP5: Comparison
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Please note this is a comparison between Version 5 by Jessie Wu and Version 4 by Jessie Wu.

To evade immune surveillance, tumors develop a hostile microenvironment that inhibits anti-tumor immunity. Recent immunotherapy breakthroughs that target the reinvigoration of tumor-infiltrating T lymphocytes (TIL) have led to unprecedented success in treating some cancers that are resistant to conventional therapy, suggesting that T cells play a pivotal role in anti-tumor immunity. In the hostile tumor microenvironment (TME), activated T cells are known to mainly rely on aerobic glycolysis to facilitate their proliferation and anti-tumor function. However, TILs usually exhibit an exhausted phenotype and impaired anti-tumor activity due to the limited availability of key nutrients (e.g., glucose) in the TME. Emerging evidence suggests that fatty acid binding protein 5 (FABP5) expression in T cells regulates T cell lipid metabolism and function. 

  • FABP5
  • lipid metabolism
  • T cells

1. Introduction

Tumor immunotherapy, particularly T lymphocyte-based immunotherapy, has achieved clinical benefits in multiple cancers, including metastatic melanoma [1], lung [2], leukemia [3], bladder [4], ovarian [5] and sarcoma [6]. There are primarily three strategies that modulate T cell activity for tumor therapies: (1) enhancing T cell/tumor recognition by genetic modification of T cell receptors (TCRs), such as transducing non-tumor specific T cells with tumor-targeting chimeric antigen receptors (CARs) to transform them into tumor-specific killers [7]; (2) adoptive cell transfer (ACT) of ex vivo expansion of tumor-infiltrating lymphocytes to promote tumor regression [8]; and (3) reinvigorating the tumor-killing activity of tumor-specific T cells in the tumor microenvironment (TME). Utilizing the immune checkpoint blockade (ICB) that targets programmed cell death protein 1 (PD-1)/its receptor (PD-L1), or cytotoxic T cell associated protein 4 (CTLA4), unleashes the anti-tumor effect of T cells in the TME, leading to therapeutic benefits in treating some tumors resistant to conventional therapy [9][10]. However, only a small percentage of cancer patients with solid tumors respond to T cell-based immunotherapy. Multiple extrinsic and intrinsic factors, including the presence of different T cell subsets, T cell activation signals, and the metabolic status of T cells in the TME, seem to be critical in determining a cancer patient’s response to ICB [11][12][13].
Lipids in T cells mainly come from two sources, endogenous lipogenesis and exogenous uptake from environment/diets. During T cell activation, enhanced uptake of glucose and amino acids can be converted to acetyl-CoA, which is further catalyzed for de novo fatty acid synthesis by acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) enzymes to fuel cell proliferation and lineage differentiation [14]. However, in T cell subsets that are less dependent on aerobic glycolysis, such as naïve T cells, Tregs and Trms, the uptake of exogenous fatty acids becomes the main lipid source to fuel their metabolism and function.
Unlike short-chain fatty acids (SCFAs) or medium-chain fatty acids (MCFAs), dietary long-chain fatty acids (LCFAs) cannot easily diffuse through plasma and organelle membranes to be oxidized. As such, FABPs facilitate these processes. It is well known that the mitochondrial carnitine shuttle system, which includes carnitine-palmitoyl transferase 1 (Cpt1), carnitine-acylcarnitine translocase (CACT) and Cpt2, helps the transfer of LCFAs from the mitochondrial outer membrane to the inner membrane for FAO [15]. Cpt1 is the main isoform in T cells, which acts as the rate-limiting step in long-chain FAO [16]. Using fatty acid binding protein 5 (FABP5)−/− mice, wresearchers have shown that the endogenous lipid content in FABP5−/− T cells is not altered, but exogenous fatty acid uptake is reduced in FABP5−/− T cells as compared to FABP5+/+ T cells. Moreover, the expression of Cpt1 is dramatically reduced in Fabp5−/− T cells [17]. These data suggest that FABP5 plays a critical role in exogenous LCFA uptake, mitochondrial lipid transport and FAO in T cells.

2. Fatty Acid Binding Protein 5 in Naïve T Cells

As long-lived cells, naïve T cells are metabolically quiescent [18]. They utilize the catabolic glucose/mitochondrial OXPHOS pathway to generate ATP for their survival. Interestingly, wresearchers recently found that T cell subsets, including naïve T cells, mainly express fatty acid chaperone FABP5 (Figure 1), suggesting that exogenous fatty acids might be involved in naïve T cell metabolism and survival. Given the growing worldwide obesity epidemic, and that obese people have elevated levels of free fatty acids [19][20][21][22], wresearchers exposed naïve T cells to various exogenous fatty acid environments and found that exogenous fatty acids can be taken up by naïve T cells to induce mitochondrial oxygen consumption [17]. Interestingly, polyunsaturated fatty acids (such as 18:2 linoleic acid, LA), but not monounsaturated fatty acids (e.g., 18:1 oleic acid, OA), activate mitochondrial ROS production leading to significant naïve T cell death. Consistent with ouresearch's observations, LA, which is enriched in nonalcoholic fatty liver disease, induces intrahepatic CD4+ T cell death via mitochondrial ROS production [23]. In the TME, the uptake of fatty acids by CD36 results in ferroptosis of tumor-infiltrating CD8+ T cells [24]. Importantly, using obese mice fed a HFD rich in 18:2 LA, wresearchers demonstrate that dietary LA is taken up by naïve T cells and oxidized to generate mitochondrial ROS in a FABP5-dependent manner [17]. As such, FABP5 deficiency successfully rescues LA-indued CD8+ T cell death, thus inhibiting mammary tumor growth in the HFD-induce obese mice. These observations suggest a pivotal role for FABP5 in mediating exogenous fatty acid uptake, mitochondrial transport and ROS-induced cell death in naïve T cells.
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Figure 1. Expression profile of FABP family members in T cells. (A) Analysis of the expression profile of fatty acid uptake related genes, including CD36, fatty acid transport protein 1-6 (FATP 1-6, encoded by SLC27A1-6) and FABP family members, in different T cell subsets using a publicly accessible dataset GSE131907. (B) Expression of FABP family members in naïve CD4+ and CD8+ T cells. Naïve CD4+ and CD8+ T cells were purified from the spleen of C57 BL/6 mice using a flow sorter. RNA was extracted for real-time PCR analysis of FABP family members.

3. Fatty Acid Binding Protein 5 in Tregs

Activation of the AMPK/FAO metabolic pathway is critical for the generation of Tregs [25]. AMPK activation by a high AMP/ATP ratio, AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) or metformin, strongly enhances mitochondrial FAO, thereby promoting the expansion of Tregs [26][27]. In peripheral induced Tregs (iTregs), elevated AMPK activity is likely to modulate Cpt1a activity and increase fatty acid transportation into mitochondria for β-oxidation [28]. The increased expression of the fatty acid translocase CD36 on the surface of Tregs enhances fatty acid uptake, thus facilitating FAO in Tregs [29]. Blocking the transportation of LCFAs into mitochondria by etomoxir (an inhibitor of Cpt1) inhibits Foxp3 expression in Tregs, while exogeneous administration of oleate/palmitate acid promotes Treg generation in vitro [26]. Given the role of FABP5 in exogenous FA uptake and mitochondrial transportation, it is likely that FABP5 plays an important role in maintaining lipid metabolism and function in Tregs.
Indeed, compared to naïve T cells, Tregs exhibit upregulated expression of FABP5. In vitro inhibition of FABP5 decreases mitochondrial cardiolipin synthesis, loss of mitochondrial cristae structure, and FAO, verifying the important role of FABP5 in mitochondrial lipid metabolism and integrity in Tregs. Interestingly, FABP5 inhibition promotes Treg immune suppression by inducing mitochondrial DNA release/type I IFN/IL-10 signaling axis [30]. Consistent with these in vitro observations, Tregs in the TME exhibited an enhanced immunosuppressive activity versus splenic Tregs due to the lack of lipid availability [30]. OurThe studies using FABP5−/− mice confirm that FABP5 deficiency protects mice from the development of experimental autoimmune encephalomyelitis (EAE) by favoring Treg differentiation and function [31]. Moreover, FABP5−/− mice are associated with an immunosuppressive TME and elevated tumor growth as compared to WT mice [32]. These data collectively support that FABP5 deficiency enhances the immune suppressive function of Tregs, thus favoring tumor evasion and growth.

4. Fatty Acid Binding Protein 5 in Memory T Cells

Unlike naïve and effector T cells, resident memory T cells, such as CD69+CD103+ Trm cells, do not circulate throughout the body [33]. They reside in specific tissues and provide efficient immune responses upon antigen re-exposure [34]. It has been shown that memory T cells rely on FAO rather than glycolysis for their long-term survival [35]. The presence of Trm cells is associated with better outcomes for individuals with ovarian, lung and breast cancers [36][37][38]. However, how FAO enhances Trm survival and anti-tumor immune response remains elusive. A recent study reports that FABPs (mainly FABP4/FABP5), which are highly expressed in skin CD8+ Trm cells, mediate exogenous palmitate uptake and mitochondrial FAO in vitro. Deletion of Fabp4/Fabp5 in CD8+ Trm cells impairs exogenous free fatty acid uptake, reduces their long-term survival and protective immune responses, suggesting that FABPs play a critical role in the survival and function of CD8+ Trm cells [16]. In line with these studies, CD69+CD103+ Trm cells in the TME of gastric adenocarcinoma highly express PD-1, and PD-1/PD-L1 blockade enhances anti-tumor function of Trm cells by increasing Fabp4/5-mediated lipid uptake and cell survival both in vitro and in vivo [39]. Moreover, CD8+ memory T cells rely on lysosomal acid lipase to mobilize FA to fuel mitochondrial FAO [40], and FABP5 has been identified as a key immunometabolic marker in tumor-infiltrating CD8+ T cells by promoting FAO and cell survival in human hepatocellular carcinoma [41]. Accumulating evidence reveals a pivotal role for FABP5 in enhancing the longevity and anti-tumor function of memory T cells by facilitating fatty acid uptake and FAO in the TME.

5. Fatty Acid Binding Protein 5 in Other T Cell Subsets

As discussed above, naïve T cells undergo dramatic metabolic alterations to develop into distinct effector T cells, including Th1, Th2 and Th17 lineages, among which the mTOR/glycolytic pathway is lineage-decisive, as inhibition of mTOR activity diminishes effector T cell development [42][43]. To accommodate the rapid proliferation of effector T cells, the synthesis of biomolecules, including de novo fatty acid synthesis, appears critical for Th1, Th2 and Th17 development. As ACCs are key enzymes that catalyze the conversion of acetyl-CoA to malonyl-CoA for endogenous synthesis of fatty acids [44], deletion of ACC1 in T cells mainly attenuates the expansion of Th17 and survival of CD8+ cells, suggesting that endogenous fatty acid synthesis is important for Th17/CD8+ T cells [45][46]. Interestingly, HFD-induced obese mice specifically augment the development of Th17 cells, but not other T cell subsets, through the ACC1/fatty acid synthesis pathway [47]. As FABP5 is associated with lipid elongation and desaturation during the process of endogenous lipid synthesis [30], it is likely that FABP5 expression in T cells favors Th17 cell development via regulating the endogenous lipid synthesis pathway. Indeed, in a mouse EAE model, deficiency of FABP5 protects mice from developing EAE symptoms by reducing Th17 cell differentiation [31]. In contrast, FABP5 expression induces Th17 polarization in both mouse models and human samples in atopic dermatitis [48]. In a Listeria monocytogenes infection model, FABP5 deficiency has no impact on the generation/maintenance of antigen-specific effector CD4+ and CD8+ T cells [49]. Collectively, these studies suggest that although ACC1 expression is generally required for all effector T cell proliferation, compared to Th1 and Th2 cells, Th17 cells appears to rely more on the de novo fatty acid synthesis pathway, which is evidenced by the reduced expansion of Th17 cells rather than other effector subsets (e.g., Th1, Th2 or CTL) in FABP5−/− mice. Given the paradox role of Th17 cells in the TME [50][51], the role of FABP5 in regulating the IL-17 axis in tumor immunotherapy warrants further investigation.

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