CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Tumor cell derived CCL20 exacerbates the immunosuppressive microenvironment by recruiting CCR6(+) Tregs in pancreatic cancer.
Tumor cell derived CCL20 exacerbates the immunosuppressive microenvironment by recruiting CCR6(+) Tregs in pancreatic cancer.
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胰腺癌预后极差，很大程度上是由于对所有当前治疗方式（包括主流免疫治疗）的耐药性。阐明免疫抑制性肿瘤微环境的机制对于开发有效的治疗策略至关重要。
在本研究中，我们发现CCL20的表达与CD8+ T细胞浸润呈负相关，并且一致的是，CCL20表达较高的患者预后更差。CCL20作为一种由SP5调控的分泌型配体蛋白，能够在肿瘤微环境中与其同源受体CCR6结合，且主要由肿瘤细胞产生，这已通过单细胞RNA测序和肿瘤组织免疫荧光染色证实。与CCL20野生型肿瘤相比，CCL20敲除肿瘤表现出生长受损、CCR6+ Tregs浸润减少，同时CD8+ T细胞浸润增加。
重要的是，这种改变的免疫浸润表型在Treg特异性CCR6敲除小鼠中被消除。此外，抑制CCR6增强了抗PD1免疫检查点阻断的疗效。
综上所述，我们的数据表明，肿瘤细胞来源的CCL20通过招募CCR6+ Tregs在胰腺癌中塑造免疫抑制性微环境，提示靶向CCL20-CCR6轴提供了一种有前景的治疗策略，尤其是与免疫检查点阻断联合使用时。
Pancreatic cancer has a dismal prognosis, largely due to resistance to all current therapeutic modalities, including prevailing immunotherapy. Deciphering the mechanisms underlying the immunosuppressive tumor microenvironment is pivotal for developing effective therapeutic strategies. In this study, we found that the expression of CCL20 is negatively correlated with the infiltration of CD8 + T cells, and consistently, patients with higher CCL20 expression have a worse prognosis.
CCL20, as a secreted ligand protein regulated by SP5, can bind to its cognate receptor CCR6 in the tumor microenvironment and is mainly produced by tumor cells, as confirmed by single-cell RNA sequencing and immunofluorescence staining of tumor tissues. Compared with CCL20 wild-type tumors, CCL20 knockout tumors exhibited impaired growth, decreased infiltration of CCR6 + Tregs, and concomitantly increased infiltration of CD8 + T cells.
Importantly, this altered immune infiltration phenotype was abolished in Treg-specific CCR6 knockout mice.
Furthermore, CCR6 inhibition potentiated the efficacy of anti-PD1 immune checkpoint blockade. Taken together, our data demonstrate that tumor cell-derived CCL20 shapes an immunosuppressive microenvironment in pancreatic cancer by recruiting CCR6 + Tregs, suggesting that targeting the CCL20-CCR6 axis offers a promising therapeutic strategy, particularly when combined with immune checkpoint blockade.
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