Regulatory T cells (Treg) are abundant in human and mouse pancreatic cancer. To understand the contribution to the immunosuppressive microenvironment, we depleted Tregs in a mouse model of pancreatic cancer. Contrary to our expectations, Treg depletion failed to relieve immunosuppression and led to accelerated tumor progression. We show that Tregs are a key source of TGFβ ligands and, accordingly, their depletion reprogramed the fibroblast population, with loss of tumor-restraining, smooth muscle actin-expressing fibroblasts. Conversely, we observed an increase in chemokines Ccl3, Ccl6, and Ccl8 leading to increased myeloid cell recruitment, restoration of immune suppression, and promotion of carcinogenesis, an effect that was inhibited by blockade of the common CCL3/6/8 receptor CCR1. Further, Treg depletion unleashed pathologic CD4+ T-cell responses. Our data point to new mechanisms regulating fibroblast differentiation in pancreatic cancer and support the notion that fibroblasts are a heterogeneous population with different and opposing functions in pancreatic carcinogenesis. SIGNIFICANCE: Here, we describe an unexpected cross-talk between Tregs and fibroblasts in pancreatic cancer. Treg depletion resulted in differentiation of inflammatory fibroblast subsets, in turn driving infiltration of myeloid cells through CCR1, thus uncovering a potentially new therapeutic approach to relieve immunosuppression in pancreatic cancer.See related commentary by Aykut et al., p. 345.This article is highlighted in the In This Issue feature, p. 327.

中文翻译：

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调节性 T 细胞耗竭会改变肿瘤微环境并加速胰腺癌的发生。


调节性 T 细胞 (Treg) 在人类和小鼠胰腺癌中含量丰富。为了了解免疫抑制微环境的贡献，我们在胰腺癌小鼠模型中耗尽了 Tregs。与我们的预期相反，Treg 耗竭未能缓解免疫抑制，并导致肿瘤进展加速。我们表明，Treg 是 TGFβ 配体的关键来源，因此，它们的消耗会重新编程成纤维细胞群，导致抑制肿瘤、表达平滑肌肌动蛋白的成纤维细胞的损失。相反，我们观察到趋化因子 Ccl3、Ccl6 和 Ccl8 的增加导致骨髓细胞募集增加、免疫抑制恢复和促进致癌作用，而这种作用可通过阻断常见的 CCL3/6/8 受体 CCR1 来抑制。此外，Treg 耗竭会释放病理性 CD4+ T 细胞反应。我们的数据指出了调节胰腺癌成纤维细胞分化的新机制，并支持以下观点：成纤维细胞是异质群体，在胰腺癌发生中具有不同且相反的功能。意义：在这里，我们描述了胰腺癌中 Tregs 和成纤维细胞之间意想不到的相互作用。 Treg 耗竭导致炎性成纤维细胞亚群分化，进而通过 CCR1 驱动骨髓细胞浸润，从而揭示了一种潜在的新治疗方法来缓解胰腺癌的免疫抑制。参见 Aykut 等人的相关评论，第 17 页。 345. 这篇文章在本期特稿中突出显示，第 345 页。 327.