Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
Cancer Res. 2023 May 15;83(10):1628-1645. doi: 10.1158/0008-5472.CAN-22-2932.
Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy.
FPR2 is a sex-dependent mediator of macrophage function in pancreatic cancer and can be targeted to reprogram macrophages and stimulate antitumor immunity in females.
性别驱动的免疫差异会影响肿瘤的进展和肿瘤微环境的状态。更深入地了解男性和女性之间的这些差异，可以为患者选择提供信息，以改善性别优化的免疫治疗。在这项研究中，单细胞 RNA 测序和蛋白质分析揭示了胰腺病变中与免疫排斥肿瘤表型和效应 T 细胞衰竭相关的髓样细胞亚群，这种髓样细胞亚群与女性的不良生存和 M2 样巨噬细胞和 T 细胞衰竭的遗传特征呈正相关。G 蛋白偶联受体甲酰肽受体 2（FPR2）介导了这些免疫抑制作用。在体外，用特异性 FPR2 拮抗剂处理髓样细胞可防止衰竭并增强效应细胞的细胞毒性。蛋白质组学分析显示，FPR2 激动剂处理后，雌性 M2 样巨噬细胞中表达高水平的免疫抑制分泌蛋白 PGE2 和半乳糖凝集素 9，富集整合素途径，减少 TNFα 和 IFNγ 等促炎信号。此外，FPR2 激动剂处理的髓样细胞仅在雌性 T 细胞中诱导 TIM3 和 PD-1 表达。用抗 TIM3 抗体治疗可逆转 T 细胞衰竭并刺激其浸润和杀伤胰腺球体的能力。在体内，与野生型（WT）雌性小鼠相比，FPR2 敲除（KO）雌性小鼠的同种胰腺肿瘤进展明显受到抑制，与 WT 和 FPR2 KO 雄性小鼠相比也是如此。在雌性小鼠中，与 WT 巨噬细胞相比，用 FPR2 KO 巨噬细胞接种肿瘤可显著减少肿瘤生长。总体而言，这项研究确定了 FPR2 在雌性中作为巨噬细胞功能的一个免疫抑制因子，强调了一种潜在的性别特异性精准免疫治疗策略。
FPR2 是胰腺癌中巨噬细胞功能的性别依赖性介质，可以作为靶点，重新编程巨噬细胞并刺激雌性的抗肿瘤免疫。
