Inhibiting The Immunosuppressive Function Of Myeloid-derived Suppressor Cells Enhanced PD-L1 Blockade-mediated Tumor Immunotherapy

Immune checkpoint inhibitors led to promising responses in the treatment of melanoma and lung cancer;owing to its success in several clinical trials,it was considered as Breakthrough of the Year 2013 in famous American journal–Science and subsequently awarded the Noble Prize in Medicine 2018.Despite the impressive responses to checkpoint inhibitors for some cancer types,a major drawback in their widespread application is the highly immunosuppressive tumor microenvironment that hinders the stimulation of tumor-infiltrating lymphocytes necessary for anti-tumor immunity.A major immunosuppressive target that had gained appreciable interest in the last few years is myeloid-derived suppressor cells(MDSCs).The accumulation of these myeloid lineage cells has been ascribed to resistance against anti-PD-L1 antibodies and could serve as a prognostic marker for treatment success.Therefore,identifying novel treatment strategies targeted at inhibiting MDSCs function is critical for successful anti-PD-L1 tumor immunotherapy.Herein we investigated if regulation of histone deacetylase(HDAC)activity or lipid metabolism in MDSCs will enhance the efficacy of PD-L1 blockade-mediated therapy in melanoma(B16F10)and Lewis lung carcinoma(LLC)-bearing mice.Our data showed that HDAC inhibitor-valproic acid(VPA)promoted the polarization of MDSCs to less suppressive monocytic-MDSCs.Notably,the combination of VPA and anti-PD-L1 therapy activated the IRF1/IRF8 transcriptional axis probably to block MDSCs immunosuppressive function through the downregulation of ARG1,IL-10,and IL-6.This promoted the reactivation of T cell's ability for enhanced TNF?production which suppressed tumor growth in mice receiving combined therapy compared to the single agents.On the other hand,we reported that uptake of polyunsaturated fatty acid(PUFA)by MDSCs led to lipid accumulation via upregulation of fatty acid transport protein 2(FATP2)and diacylglycerol transferase 1(DGAT1).Lipidomics analysis revealed the exact lipid species accumulated in MDSCs from tumor-bearing mice to be phospholipids and triglycerides(TAG).Inhibiting FATP2 or DGAT1 either in vitro or in vivo reduced neutral lipid level thus led to decreased MDSCs accumulation,reduced immunosuppressive function of MDSCs,and increased T cell proportion.Notably,blockade of either FATP2 or DGAT1 expression abrogated B16F10 or LLC tumor growth in mice.On the contrary,FATP2 or DGAT1 blockade in immunocompromised mice failed to reduce B16F10-tumor progression,this suggests that the effect of the FATP2 or DGAT1 inhibition may be immune dependent.Remarkably,either FATP2 or DGAT1 inhibition provided additional therapeutic benefits to anti-PD-L1 antibodies and delayed tumor growth in immune-competent mice.Mechanistically,blockade of FATP2 or DGAT1 expression in MDSCs promoted anti-PD-L1 tumor immunotherapy via increased TNF?,IFN-?,and CD107a expression in tumor-infiltrating CD8~+T cells.Altogether,our study identified the potential of VPA in combination with anti-PD-L1antibody and unreported lipid metabolic targets(FATP2 and DGAT1)in MDSCs that promises a novel therapeutic option in clinical settings to augment anti-PD-L1 cancer immunotherapy.