Type I collagen deletion in α SMA + myofibroblasts enhances immune suppression and accelerates progression of pancreatic cancer-猫眼课题宝

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2021

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Yang Chen;Jiha Kim;Sujuan Yang;Huamin Wang;Chang-Jiun Wu;H. Sugimoto;Valerie S. LeBleu;R. Kalluri-R.-Kal

胰腺导管腺癌（PDAC）的间质促纤维增生反应涉及I型胶原（Col 1）的显著积聚。然而，Col 1在PDAC进展中的精确分子和机制贡献仍然未知。活化的胰腺星状细胞（PSC）/ α SMA +肌成纤维细胞是PDAC基质中Col 1的主要贡献者。我们采用双重组酶遗传小鼠模型的自发PDAC删除Col 1特异性肌成纤维细胞。这导致总基质Col 1含量显著降低，并加速PanIN和PDAC的出现，降低总生存期。机制研究表明，Coll缺失通过SOX 9导致癌细胞中的Cxcl 5上调。Cxcl 5的增加与骨髓源性抑制细胞（MDSC）的募集和CD 8 + T细胞的抑制相关，这可以通过CXCR 2和CCR 2的联合抑制与受抑制的PDAC进展来减弱。总之，我们的结果揭示了肌成纤维细胞衍生的Col 1在调节肿瘤免疫和抑制PDAC进展中的基本作用。图形摘要和W. PDAC章节和批准：H.W.单细胞RNA-seq分析：S.Y.和Y.C.公司。资源：R.K.监督：Y.C.，H. W.，S.Y.，VSL，和R.K.验证：Y.C.写作-草稿：Y.C.和R.K. J. K.，S.Y.，H. W.，C.- J. Typesetting，Chen et al.确定使用双重组酶小鼠模型在α SMA +肌成纤维细胞中缺失I型胶原（Col 1）可降低基质Col 1含量并加速胰腺癌进展。Col 1缺失可促进CD 206 + F4/80 + ARG 1+髓系白血病衍生抑制细胞的募集，这可通过联合抑制CXCR 2和CCR 2而减弱。编码癌细胞衍生的ECM蛋白的基因。肌成纤维细胞中Col 1缺失与MDSC数量增加相关，MDSC特异性表达高水平的CD 206、F4/80、精氨酸酶-1、CCL 2和白细胞介素-18，并可能有助于PDAC中的免疫抑制微环境。这些MDSC可以通过CD 206和CD 206进一步抑制T和B淋巴细胞功能。机制研究表明，增加的CD 206 + F4/80 + Arg 1 + MDSC募集可能是由于基质Col 1含量降低，其随后诱导癌细胞中S 0X 9调节的Cxcl 5表达。我们的研究清楚地表明，由成纤维细胞产生的Col 1可以在功能上影响PDAC的免疫特征，并且抑制CD 206 + F4/80 + Arg 1 + MDSC募集可以抑制PDAC的进展。进行潜在卡方χ 2分析，比较TCGA PDAC队列和/或MDACC PDAC队列中AJCC肿瘤分期和肿瘤分化状态的病例分布。TCGA PDAC群组样品中指示基因的表达水平基于RNA Seq V2 RSEM数据。从cBioPortal下载TCGA数据对于基于IL 18表达的存活分析，基于中值IL 18表达水平将具有可用OS数据和RNA-seq数据的患者（n = 177）分层为IL 18-高（n = 90）和IL 18-低（n = 87）组。类似地，对于基于CXCL 6（小鼠Cxcl 5的人类同源物）表达的存活分析，基于中值CXCL 6表达水平将患者（n = 177）分层为CXCL 6-高（n = 90）和CXCL 6-低（n = 87）组。绘制Kaplan-Meier图用于生存分析，并使用对数秩Mantel-Cox检验评估统计学差异。数据符合每个统计检验的假设，其中方差不相等（通过F检验确定），应用Welch不等方差校正。P值< 0.05为有统计学意义。误差条表示平均值的标准误差（S.E.M.）当对多个视野进行平均以产生每个视野的单个值时

SUMMARY Stromal desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC) involves significant accumulation of type I collagen (Col1). However, the precise molecular and mechanistic contribution of Col1 in PDAC progression remains unknown. Activated pancreatic stellate cells (PSCs)/ α SMA + myofibroblasts are major contributors of Col1 in the PDAC stroma. We employ a dual-recombinase genetic mouse model of spontaneous PDAC to delete Col1 specifically in myofibroblasts. This results in significant reduction of total stromal Col1 content and accelerates the emergence of PanINs and PDAC, decreasing overall survival. Mechanistic studies suggest that Col1 deletion leads to Cxcl5 upregulation in cancer cells via SOX9. Increase in Cxcl5 is associated with recruitment of myeloid-derived suppressor cells (MDSCs), and suppression of CD8 + T cells, which can be attenuated by combined suppression of CXCR2 and CCR2 with restrained PDAC progression. Taken together, our results unravel the fundamental role of myofibroblast-derived Col1 in regulating tumor immunity and restraining PDAC progression. Graphical Abstract and and W. PDAC sections and approvals : H.W. Single-cell RNA-seq analysis: S.Y. and Y.C. Resources: R.K. Supervision: Y.C., H.W., S.Y., V.S.L., and R.K. Validation: Y.C. Writing - draft: Y.C. and R.K. J.K., S.Y., H.W., C.-J. typesetting, Chen et al. identify that the deletion of type I collagen (Col1) in α SMA + myofibroblasts using dual-recombinase mouse models decreases stromal Col1 content and accelerates progression of pancreatic cancer. Col1 deletion promotes the recruitment of CD206 + F4/80 + ARG1 + myeloid derived suppressor cells, which can be attenuated by combined inhibition of CXCR2 and CCR2. of genes encoding cancer cell-derived ECM proteins. Col1 deletion in myofibroblasts is associated with increased number of MDSCs, which specifically express high levels of CD206, F4/80, argninase-1, CCL2, and interleukin-18, and likely contribute to the immunosuppressive microenvironment in PDAC. These MDSCs can further suppress T and B lymphocyte function via arginase-1 and CD206. Mechanistic studies indicate that the increased CD206 + F4/80 + Arg1 + MDSC recruitment could result from the decreased stromal Col1 content, which subsequently induces the SOX9-regulated expression of Cxcl5 in cancer cells. Our study clearly suggests that Col1 made by fibroblasts can functionally impact immune profile of PDAC and suppression of CD206 + F4/80 + Arg1 + MDSC recruitment can restrain PDAC progression. into potential Chi-square χ 2 analyses were performed comparing the case distribution of AJCC tumor stages and tumor differentiation status among TCGA PDAC cohort and/or MDACC PDAC cohort. The expression levels of indicated genes among TCGA PDAC cohort samples were based on the RNA Seq V2 RSEM data. TCGA data were downloaded from cBioPortal For the survival analysis based on IL18 expression, patients with available OS data and RNA-seq data (n = 177) were stratified into IL18-high (n = 90) and IL18-low (n = 87) groups based on the median IL18 expression level. Similarly, for the survival analysis based on CXCL6 (the human homolog of mouse Cxcl5) expression, patients (n = 177) were stratified into CXCL6-high (n = 90) and CXCL6-low (n = 87) groups based on the median CXCL6 expression level. Kaplan-Meier plots were drawn for survival analysis and the log rank Mantel-Cox test was used to evaluate statistical differences. Data met the assumptions of each statistical test, where variance was not equal (determined by an F-test) Welch’s correction for unequal variances was applied. A P value < 0.05 was considered statistically significant. Error bars represented standard error of the mean (S.E.M.) when multiple visual fields were averaged to produce a single value for each which was then averaged again to represent the mean bar for the group in each

Type I collagen deletion in α SMA + myofibroblasts enhances immune suppression and accelerates progression of pancreatic cancer

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