Interferon gamma inhibits CXCL8-CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer
Interferon gamma inhibits CXCL8-CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer
复制标题
干扰素γ抑制CXCL8-CXCR2轴介导的肿瘤相关巨噬细胞肿瘤运输并增强胰腺癌中的抗PD1疗效
DOI：
10.1136/jitc-2019-000308
复制
发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Yan, Qiang
中科院分区：
文献类型：
--
作者：
Zhang, Mingjie;Huang, Lifeng;Yan, Qiang
研究背景胰腺癌(PC)是消化系统常见的恶性肿瘤，具有预后差、早期转移等特点。肿瘤免疫逃逸在PC的进展中起着重要作用。程序性死亡1(PD1)阻断疗法是治疗PC的一种有前景的治疗方法，但迄今尚未取得显著的临床效果。干扰素-γ是一种可溶性的二聚体细胞因子，与肿瘤免疫监视和细胞毒作用密切相关。干扰素-γ可抑制PC中的多种肿瘤细胞因子，如CXCL8。在本研究中，我们观察了抗PD_1和干扰素-γ联合治疗PC的疗效。方法用BxPC-3和PANC-1人PC细胞系建立小鼠PC模型。采集44例前列腺癌患者的血液标本和36例手术切除标本。采用χ2检验、双尾非配对t检验或Kaplan-Meier生存分析计算p值。结果PD1/PD-L1信号通路在PC荷瘤小鼠体内呈高表达。如果在肿瘤接种后早期启动抗PD1，则可防止肿瘤生长；然而，延迟抗PD1治疗显示出有限的益处。小鼠PC模型优先扩增CXCR2+CD68+巨噬细胞，这些细胞具有免疫抑制性质(M2极化)。PC肿瘤过度表达CXCL8，肿瘤来源的CXCL8缺乏抑制了CXCR2+CD68+巨噬细胞的转运。干扰素-γ抑制肿瘤来源的CXCL8的表达，并与干扰素-γ联合治疗显示明显的抗肿瘤作用。因此，我们得出结论，小鼠CXCR2+CD68+巨噬细胞通过肿瘤来源的CXCL8转运到PC肿瘤并介导局部免疫抑制，这限制了PD1阻断治疗的疗效。干扰素-γ通过阻断CXCL8-CXCR2轴来增强抗PD1的效果，从而抑制肿瘤来源的CXCL8和CXCR2+CD68+巨噬细胞的肿瘤转运。人类PC也会产生高水平的CXCL8。PC患者外周血和肿瘤浸润性CD68+巨噬细胞上CXCR2表达升高，与肿瘤分期和预后不良有关。结论干扰素-γ通过阻断CXCL8-CXCR2轴，阻止CXCR2+CD6 8+巨噬细胞的转运，从而提高PD1阻断治疗的疗效。
Background Pancreatic cancer (PC) is a common malignancy of the digestive system and is characterized by poor prognosis and early metastasis. Tumor immune escape plays an important role in PC progression. Programmed death 1 (PD1) blockade therapy is a promising treatment for patients with PC, but is yet to achieve significant clinical effects so far. Interferon gamma (IFN-γ) is a soluble dimeric cytokine that is closely associated with tumor immune surveillance and cytotoxicity. IFN-γ suppresses a variety of tumor-derived cytokines in PC, such as CXCL8. In the present study, we investigated the therapeutic efficacy of combined anti-PD1 and IFN-γ treatment in PC. Methods BxPC-3 and Panc-1 human PC cell lines were used to construct a murine PC model. Blood samples (n=44) and surgical resection specimens (n=36) from human patients with PC were also collected. χ2 test, two-tailed unpaired t-test or Kaplan-Meier survival analysis was used to calculate p values. Results PD1/PD-L1 signaling was overexpressed in PC tumor-bearing mice. Anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 treatment showed limited benefit. Murine PC model had a preferential expansion of CXCR2+CD68+ macrophages, and these cells showed an immunosuppressive nature (M2 polarization). PC tumors overexpressed CXCL8 and tumor-derived CXCL8 deficiency prohibited the trafficking of CXCR2+CD68+ macrophages. IFN-γ suppressed the expression of tumor-derived CXCL8, and combined with IFN-γ treatment, delayed anti-PD1 treatment showed significant antitumor effects. Thus, we conclude that murine CXCR2+CD68+ macrophages traffic to PC tumors by tumor-derived CXCL8 and mediate local immunosuppression, which limits the efficacy of PD1 blockade therapy. IFN-γ suppresses tumor-derived CXCL8 and inhibits the tumor trafficking of CXCR2+CD68+ macrophages by blocking the CXCL8–CXCR2 axis to enhance anti-PD1 efficacy. Human PC also produces high levels of CXCL8. Patients with PC present elevated CXCR2 expression on peripheral and tumor-infiltrating CD68+ macrophages, which are associated with advanced tumor stage and poor prognosis. Conclusion Our findings suggest that IFN-γ is a translatable, therapeutic option to improve the efficacy of PD1 blockade therapy by preventing trafficking of CXCR2+CD68+ macrophages via blocking the CXCL8–CXCR2 axis.