Regulation of ROS in myeloid-derived suppressor cells through targeting fatty acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy

Abstract

Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy against the PD-1/PD-L1 axis, it induces sustained responses in a sizeable minority of cancer patients due to the activation of immunosuppressive factors such as myeloid-derived suppressor cells (MDSCs). Inhibiting the immunosuppressive function of MDSCs is critical for successful cancer ICB therapy. Interestingly, lipid metabolism is a crucial factor in modulating MDSCs function. Fatty acid transport protein 2 (FATP2) conferred the function of PMN-MDSCs in cancer via the upregulation of arachidonic acid metabolism. However, whether regulating lipid accumulation in MDSCs by targeting FATP2 could block MDSCs reactive oxygen species (ROS) production and enhance PD-L1 blockade-mediated tumor immunotherapy remains unexplored. Here we report that FATP2 regulated lipid accumulation, ROS, and immunosuppressive function of MDSCs in tumor-bearing mice. Tumor cells-derived granulocyte macrophage-colony stimulating factor (GM-CSF) induced FATP2 expression in MDSCs by activation of STAT3 signaling pathway. Pharmaceutical blockade of FATP2 expression in MDSCs by lipofermata decreased lipid accumulation, reduced ROS, blocked immunosuppressive activity, and consequently inhibited tumor growth. More importantly, lipofermata inhibition of FATP2 in MDSCs enhanced anti-PD-L1 tumor immunotherapy via the upregulation of CD107a and reduced PD-L1 expression on tumorinfiltrating CD8 + T-cells. Furthermore, the combination therapy blocked MDSC's suppressive role on Tcells thereby enhanced T-cell's ability for the production of IFN-γ. These findings indicate that FATP2 plays a key role in modulating lipid-induced ROS in MDSCs and targeting FATP2 in MDSCs provides a novel therapeutic approach to enhance anti-PD-L1 cancer immunotherapy.

Metabolic reprogramming of myeloid-derived suppressor cells: An innovative approach confronting challenges

“…MDSCs treated with the PUFA linoleic acid exhibit a stronger inhibitory effect than the saturated fatty acid palmitic acid 70 . Pharmaceutic blockade of FATP2 by lipofermata reduced arachidonic acid uptake and PGE2 expression in MDSCs 139 . Genetic ablation of the fatty acid translocase CD36 also mitigated oxidative metabolism in the T‐MDSCs through STAT3 and STAT5 signaling 140 .…”

“…70 Pharmaceutic blockade of FATP2 by lipofermata reduced arachidonic acid uptake and PGE2 expression in MDSCs. 139 Genetic ablation of the fatty acid translocase CD36 also mitigated oxidative metabolism in the T-MDSCs through STAT3 and STAT5 signaling. 140 The FAO inhibitor etomoxir markedly decreased the ability of MDSCs to block T cells proliferation.…”

A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment

“…Adeshakin and colleagues previously demonstrated the role of polyunsaturated fatty acids (PUFA) in MDSC expansion and immunosuppression activity in tumours via JAK/STAT3 pathway activation [205], and they recently proposed a new role for FATP2 in regulating MDSC immunosuppressive activity through lipid-accumulationinduced ROS. Indeed, the small molecule inhibitor lipofermata was identified as a new approach to overcome resistance to anti-PD-L1 therapies that rely entirely upon the GM-CSF/STAT3/STAT5/FATP2 axis [206]. Of note, lipofermata upregulates the expression of NRF2 both in tumour-bearing mice and patients, thus suggesting that FATP2 regulates immunosuppressive MDSC functions through an anti-oxidative signalling pathway.…”

Myeloid-Derived Suppressor Cells: Implications in the Resistance of Malignant Tumors to T Cell-Based Immunotherapy

“…ROS inhibited T-cell immune responses by restricting interactions between TCR and MHC, whereas ROS inhibitors could reverse the suppressive effect of MDSCs on T cells (Liu et al, 2015). Moreover, elevated ROS levels suppressed their differentiation to mature myeloid cells, enhancing the recruitment of MDSCs and forming a signaling cascade (Adeshakin et al, 2021). Intriguingly, MDSCs were demonstrated to salvage the harmful effect of ROS by expressing the nuclear factor erythroid 2-related factor 2 (Nrf2), an transcription factor mediating cellular antioxidant response (Beury et al, 2016).…”