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IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages.

ABSTRACT: In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identified elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These findings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in gastric cancer patients.

SUBMITTER: Zhang J

PROVIDER: S-EPMC11246528 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages.

Zhang Jiayu J Dong Yu Y Yu Shan S Hu Keshu K Zhang Lingyun L Xiong Min M Liu Mengling M Sun Xun X Li Suyao S Yuan Yitao Y Zhang Chi C Zhu Mengxuan M Wei Yichou Y Zhu Yanjing Y Yu Yiyi Y Zhang Pengfei P Liu Tianshu T

Cell death & disease 20240713 7

In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing ...[more]

PMID: 39003253

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Project description:Background:Tumor-associated macrophage (TAM) is emerging as one of the important complications in cancer promotion. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, plays an active role in promoting M2 macrophage differentiation (TAMs are M2-like phenotypes). In this study, we aimed to evaluate that IL-17 stimulates key phenotypic and functional signatures of M2 macrophages associated with cancer progression in non-small-cell lung cancer (NSCLC) patients. Patients and methods:The markers and cytokines of M2 macrophages were detected in THP-1-derived macrophages and mouse peritoneal macrophages treated with IL-17. The activation of nuclear factor kappa B (NF-?B) and nuclear localization of p65 in IL-17-treated cells were investigated. The BAY11-7082 inhibitor and the siRNA of p65 were used to block the NF-?B activation. A total of 85 patients who underwent surgery for histologically verified NSCLC were enrolled in this study. The expression of IL-17 and M2 macrophage markers were assessed by immunostaining. Survivals were estimated using the Kaplan-Meier method. Results:The CD163 and CD206 cell surface markers and transforming growth factor beta (TGF-?), vascular endothelial growth factor (VEGF) and IL-10 of M2 macrophages were significantly increased in IL-17-treated THP-1-derived macrophages in a dose-dependent manner. IL-17 increased the mRNA levels of Arginase I and Fizz1, the phosphorylation of IkB? and nuclear localization of p65 (a subunit of NF-?B). The BAY11-7082 abrogated IL-17-induced CD206 and CD163 expression, TGF-?, VEGF, IL-10, Arginase I and Fizz1 expression and p65 nuclear translocation. Further experiments showed that IL-17 induced the expression of CD206, CD163, Arginase I, Fizz1 and Ym1 in mouse peritoneal macrophages that were inhibited by siRNA of p65. The immunostaining experiments on human NSCLC tissues indicated that high IL-17 expression was significantly correlated with CD163 and c-Maf. The intratumoral IL-17+ CD163+ c-Maf+ cells were associated with NSCLC progression. Conclusion:IL-17 stimulated macrophages to M2-like phenotypes via NF-?B activation. IL-17 may be a potential therapeutic target for NSCLC.

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IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages.

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IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages.

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