Purpose: Immunotherapy has demonstrated durable clinical responses in various cancers by disinhibiting the immune system, largely attributed to the success of immune-checkpoint blockade. However, there are still subsets of patients across multiple cancers not showing robust responses to these agents and one significant barrier to their efficacy may be the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. In this study, we demonstrated that functional inhibition of MDSCs with (3 R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (TIMO), a potent PI3Kδ/γ inhibitor, enhanced the therapeutic efficacy of anti-PD1 antibody in the tumor model.Materials and methods: A syngeneic ovarian tumor model was established. MDSCs from the peripheral blood and tumor parenchyma were analyzed by flow cytometry. Proliferation and killing effects of T-lymphocytes were measured. IFNγ production was measured by ELISA assay. qPCR and western blot were used to detect the gene and protein expression. Furthermore, the therapeutic effects of TIMO combined with anti-PD1 antibody were assessed by the tumor model.Results: Our data demonstrated that inhibition of granulocytic myeloid-derived suppressor cells (G-MDSCs) function with TIMO could overcome MDSCs-mediated immunosuppression and promote antigen-specific T-lymphocyte responses, resulting in the restoration of cytotoxic T cell-mediated tumor control. We further demonstrated that TIMO and anti-PD1 combination therapy promoted tumor growth control in a syngeneic ovarian tumor model.Conclusions: Our results provided proof of concept for a new combination strategy involving the use of a selective inhibitor of PI3Kδ/γ to inhibit the function of MDSCs to enhance tumor responses to immune checkpoint blocking antibodies.

中文翻译：

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（3R）-5,6,7-三羟基-3-异丙基-3-甲基异色满-1-酮通过抑制PI3Kδ/γ增强抗PD1抗体的治疗效果。

目的：通过抑制免疫系统，免疫疗法已在多种癌症中表现出持久的临床反应，这在很大程度上归功于免疫检查点封锁的成功。但是，仍然有多种癌症的患者亚组未显示出对这些药物的强烈反应，其功效的一个重要障碍可能是将髓样来源的抑制细胞（MDSC）募集到肿瘤微环境中。在这项研究中，我们证明了有效的PI3Kδ/γ抑制剂（3 R）-5,6,7-三羟基-3-异丙基-3-甲基异色满-1-酮（TIMO）对MDSC的功能抑制作用可增强治疗效果抗PD1抗体在肿瘤模型中的作用。材料与方法：建立了同基因卵巢肿瘤模型。通过流式细胞术分析来自外周血和肿瘤实质的MDSC。测量了T淋巴细胞的增殖和杀伤作用。通过ELISA测定法测量IFNγ的产生。用qPCR和western blot检测基因和蛋白表达。此外，通过肿瘤模型评估了TIMP与抗PD1抗体的联合治疗效果。结果：我们的数据表明，TIMO抑制粒细胞髓样抑制细胞（G-MDSCs）的功能可以克服MDSCs介导的免疫抑制并促进抗原特异性的T淋巴细胞反应，从而导致细胞毒性T细胞介导的肿瘤控制的恢复。我们进一步证明了TIMO和抗PD1联合疗法在同基因卵巢肿瘤模型中促进了肿瘤生长的控制。