Blocking CX3CR1+ Tumor-Associated Macrophages Enhances the Efficacy of Anti-PD1 Therapy in Hepatocellular Carcinoma.

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Xiaonan Xiang, Kai Wang, Hui Zhang, Haibo Mou, Zhixiong Shi, Yaoye Tao, Hongliang Song, Zhengxing Lian, Shuai Wang, Di Lu, Xuyong Wei, Haiyang Xie, Shusen Zheng, Jianguo Wang, Xiao Xu
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Abstract

The efficacy of immune checkpoint inhibitors in the treatment of hepatocellular carcinoma (HCC) remains limited, highlighting the need for further investigation into the mechanisms underlying treatment resistance. Accumulating evidence indicates that tumor-associated macrophages (TAM) within the tumor microenvironment demonstrate a key role in immune evasion and treatment resistance. This study explored the role of TAMs in the HCC tumor microenvironment. Our findings reveal that TAMs expressing CX3C motif chemokine receptor 1 (CX3CR1) induced T-cell exhaustion through IL27 secretion in orthotopic models of HCC following treatment with anti-PD1. Moreover, we identified prostaglandin E2 (PGE2), released by immune-attacked tumor cells, as a key regulator of TAM transition to a CX3CR1+ phenotype. To augment the therapeutic response to anti-PD1 therapy, we propose targeting CX3CR1+ TAMs in addition to anti-PD1 therapy. Our study contributes to the understanding of the role of TAMs in cancer immunotherapy and highlights potential clinical implications for HCC treatment. The combination of targeting CX3CR1+ TAMs with anti-PD1 therapy holds promise for enhancing the efficacy of immunotherapeutic interventions in patients with HCC.

阻断CX3CR1+肿瘤相关巨噬细胞可增强肝细胞癌抗PD-1疗法的疗效
免疫检查点抑制剂(ICI)治疗肝细胞癌(HCC)的疗效仍然有限,这凸显了进一步研究其潜在机制的必要性。越来越多的证据表明,肿瘤微环境(TME)中的肿瘤相关巨噬细胞(TAMs)与免疫逃避和耐药性有关。本研究旨在探讨 TAMs 在 HCC TME 中的作用。我们的研究结果表明,CX3C motif趋化因子受体1(CX3CR1)阳性的TAMs通过分泌白细胞介素-27(IL-27)参与了诱导T细胞衰竭的关键过程,为了解抗PD-1疗法在HCC中疗效不佳的机制提供了宝贵的见解。此外,我们还发现免疫攻击的肿瘤细胞释放的前列腺素 E2 (PGE2) 是 CX3CR1+ TAM 表型转变的关键调节因子。为了增强目前抗 PD-1 疗法的治疗效果,我们提出了一种创新的治疗策略,即在抗 PD-1 治疗的同时靶向 CX3CR1+ TAMs。总之,我们的研究有助于人们了解 TAMs 在癌症免疫疗法中的作用,并强调了其对 HCC 治疗的潜在临床意义。将靶向 CX3CR1+ TAMs 与抗 PD-1 治疗相结合有望提高 HCC 患者免疫治疗干预的疗效。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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