Abstract:The production of nitric oxide (NO) is a key feature of immunosuppressive myeloid cells, which impair T cell activation and proliferation via reversibly blocking interleukin-2 receptor signaling. NO is mainly produced from L-arginine by inducible NO synthase (iNOS). Moreover, L-arginine is an essential element for T cell proliferation and behaviors. Impaired T cell function further inhibits anti-tumor immunity and promotes tumor progression. Previous studies indicated that radiotherapy activated anti-tumor imm… Show more
“…Increased ROS drives MDSCs immunosuppressive activity on T-cells as well as inhibit its differentiation to other myeloid cells [39]. Elevated level of ROS is a major characteristic of MDSCs present in tumor-bearing mice and cancer patients [40][41][42]. The immune-suppressive function of MDSCs in tumorbearing mice and cancer patients can be overcome by blocking ROS production in MDSCs [43].…”
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.
“…Increased ROS drives MDSCs immunosuppressive activity on T-cells as well as inhibit its differentiation to other myeloid cells [39]. Elevated level of ROS is a major characteristic of MDSCs present in tumor-bearing mice and cancer patients [40][41][42]. The immune-suppressive function of MDSCs in tumorbearing mice and cancer patients can be overcome by blocking ROS production in MDSCs [43].…”
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.
“…In human malignancies, iNOS co-expression with COX-2 is often observed [ 7 , 17 ]. On the other hand, NO has been shown to impede cellular immunity, and iNOS inhibitors improve efficiency of immunotherapy and radiotherapy in mice by enhancing T and NK cell infiltration and activity [ [18] , [19] , [20] , [21] ]. The specific role of NO activity on macrophages, major drivers of tumour-associated inflammation, remains to be fully elucidated.…”
“…Treatment of WT mice with the iNOS inhibitor 1400W, which leads to a specific inhibition of NO produced by M 58 , led to decreased percentages of both peroxynitrite + LT-HSC and apoptotic LT-HSC and to a better recovery of LT-HSC number 21 days post-TBI. A 1400W treatment combined with radiotherapy increases survival and delays or suppresses tumor growth in pancreas, lung and breast cancer 59,60 . Our results strengthened its use in cancer treatment as we showed that 1400W treatment also protected LT-HSC from potential deleterious effects of radiotherapy.…”
Bone marrow resident macrophages interact with a population of long-term hematopoietic stem cell (LT-HSC) but their role on LT-HSC properties after stress is not well defined. Here, we show that a 2 Gy total body irradiation (TBI)-mediated death of LT-HSC is associated with increased percentages of LT-HSC with reactive oxygen species (ROS) and of bone marrow resident macrophages producing nitric oxide (NO), resulting in an increased percentage of LT-HSC with endogenous cytotoxic peroxynitrites. Pharmacological or genetic depletion of bone marrow resident macrophages impairs the radio-induced increases in the percentage of both ROS+ LT-HSC and peroxynitrite+ LT-HSC and results in a complete recovery of a functional pool of LT-HSC. Finally, we show that after a 2 Gy-TBI, a specific decrease of NO production by bone marrow resident macrophages improves the LT-HSC recovery, whereas an exogenous NO delivery decreases the LT-HSC compartment. Altogether, these results show that bone marrow resident macrophages are involved in the response of LT-HSC to a 2 Gy-TBI and suggest that regulation of NO production can be used to modulate some deleterious effects of a TBI on LT-HSC.
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