卵巢腺癌（OVAD）经常转移到腹腔并通过形成腹水表现出来，这构成了一个促进肿瘤的微环境。在腹腔中，存在两种发育、表型和功能上不同的巨噬细胞亚群，免疫能力强的大腹腔巨噬细胞（LPM）和免疫抑制性的小腹腔巨噬细胞（SPM）。由于过氧化物酶体增殖物激活受体γ（PPARγ）是参与巨噬细胞分化的关键因子，并且与CCAAT增强子结合蛋白β（C/EBPβ）合作，后者是SPM向LPM分化的转录因子，PPARγ还可能参与SPM/LPM平衡的调节，并且可能是一个有前途的治疗靶点。 为评估PPARγ内源配体15(S)-羟基二十四碳烯酸（HETE）对卵巢肿瘤生长的影响，我们将15(S)-HETE腹腔内注射到小鼠卵巢癌模型中。该实验模型是在同种基因C57BL/6雌性小鼠的腹腔内注射表达荧光素的ID8细胞。这个ID8同位型小鼠模型是一个经过充分验证的末期上皮性卵巢腺癌的实验模型。使用活体成像系统监测肿瘤进展。通过流式细胞术和细胞分选分析腹水中的腹腔免疫细胞。为了确定15(S)-HETE在肿瘤发展中的影响是否通过巨噬细胞介导，我们通过脂质体克洛德龙酸注射来消耗这些细胞。为了进一步解剖15(S)-HETE如何介导其抗肿瘤作用，我们评估了在携带基因选择性缺失PPARγ的骨髓源性细胞和缺乏重组激活基因Rag2的小鼠肿瘤负荷。最后，为了验证我们的数据在人体中的有效性，我们从卵巢腺癌患者腹水中分离和处理巨噬细胞。 在这里，我们展示了在小鼠卵巢癌模型中，15(S)-HETE治疗显著抑制了肿瘤生长，与SPM向LPM的分化和LPM在腹腔中的寄居相关。我们证明了C/EBPβ和GATA6在SPM向LPM分化和LPM腹腔寄生过程中通过PPARγ激活发挥了重要作用。此外，这种SPM向LPM转变与效应器/调节性T细胞比例的增加相关。最后，我们报告了15(S)-HETE减弱了来自卵巢肿瘤相关腹水巨噬细胞的免疫抑制性特性。 总之，这些结果表明PPARγ是限制卵巢腺癌发展的潜在治疗靶点，并加强了PPARγ激动剂在抗癌治疗中的使用。©作者（或他们的雇主）2023年。根据CC BY-NC许可进行再使用。由BMJ出版。

Ovarian adenocarcinoma (OVAD) frequently metastasizes to the peritoneal cavity and manifests by the formation of ascites, which constitutes a tumor-promoting microenvironment. In the peritoneal cavity, two developmentally, phenotypically and functionally distinct macrophage subsets, immunocompetent large peritoneal macrophages (LPM) and immunosuppressive small peritoneal macrophages (SPM), coexist. Because peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor participating in macrophage differentiation and cooperates with CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor essential for SPM-to-LPM differentiation, PPARγ could be also involved in the regulation of SPM/LPM balance and could be a promising therapeutic target.To evaluate the 15(S)-hydroxyeicosatetraenoic acid (HETE), a PPARγ endogenous ligand, impact on ovarian tumor growth, we intraperitoneally injected 15(S)-HETE into a murine ovarian cancer model. This experimental model consists in the intraperitoneally injection of ID8 cells expressing luciferase into syngeneic C57BL/6 female mice. This ID8 orthotopic mouse model is a well-established experimental model of end-stage epithelial OVAD. Tumor progression was monitored using an in vivo imaging system. Peritoneal immune cells in ascites were analyzed by flow cytometry and cell sorting. To determine whether the impact of 15(S)-HETE in tumor development is mediated through the macrophages, these cells were depleted by injection of liposomal clodronate. To further dissect how 15(S)-HETE mediated its antitumor effect, we assessed the tumor burden in tumor-bearing mice in which the PPARγ gene was selectively disrupted in myeloid-derived cells and in mice deficient of the recombination-activating gene Rag2. Finally, to validate our data in humans, we isolated and treated macrophages from ascites of individuals with OVAD.Here we show, in the murine experimental model of OVAD, that 15(S)-HETE treatment significantly suppresses the tumor growth, which is associated with the differentiation of SPM into LPM and the LPM residency in the peritoneal cavity. We demonstrate that C/EBPβ and GATA6 play a central role in SPM-to-LPM differentiation and in LPM peritoneal residence through PPARγ activation during OVAD. Moreover, this SPM-to-LPM switch is associated with the increase of the effector/regulatory T-cell ratio. Finally, we report that 15(S)-HETE attenuates immunosuppressive properties of human ovarian tumor-associated macrophages from ascites.Altogether, these results promote PPARγ as a potential therapeutic target to restrain OVAD development and strengthen the use of PPARγ agonists in anticancer therapy.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.