Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma.
Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma.
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DOI：
10.1053/j.gastro.2013.07.025
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发表时间：
2013-11
期刊：
影响因子：
29.4
通讯作者：
Kocher HM
中科院分区：
文献类型：
--
作者：
Ene-Obong A;Clear AJ;Watt J;Wang J;Fatah R;Riches JC;Marshall JF;Chin-Aleong J;Chelala C;Gribben JG;Ramsay AG;Kocher HM
胰腺导管腺癌(PDAC)以结缔组织增生性微环境为特征，含有多种不同的免疫细胞。活化的胰星状细胞(PSCs)参与了促结缔组织发育。我们调查了不同类型的免疫细胞是否对不同的基质细胞进行了不同程度的渗透。我们使用组织芯片分析来比较不同的胰胆管病变组织(胰腺癌、壶腹癌、胆管癌、粘液性囊性肿瘤、慢性炎症和慢性胰腺炎)以及瘤旁间质(距肿瘤100μm)和胰腺间质的免疫细胞浸润。我们调查了免疫渗透与患者生存时间之间的关系。我们分析了LSL-KrasG12D/+、LSL-Trp53R172H/+、PDX-1-CRE(KPC)小鼠的T细胞迁移和肿瘤侵袭，以及全反式维甲酸(ATRA)对这些过程的影响。来自两组独立患者的PDAC样本的瘤旁间隔中，与全间质间隔相比，含有更多的髓过氧化物酶+和CD68+细胞。然而，PDAC的瘤旁室含有的CD8+、FoxP3+、CD56+或CD20+细胞比泛层室少，这在壶腹癌和胆管癌中是不存在的。瘤旁CD8+T细胞密度高的PDAC患者生存时间长于低密度患者。在KPC小鼠中，给予全反式维甲酸，使PSCs静止，增加了瘤旁间隔中CD8+T细胞的数量。我们发现，活化的PSCs表达细胞因子、趋化因子和黏附分子，调节T细胞的迁移。体外迁移实验显示，与静止的PSC或肿瘤细胞相比，PDAC患者的CD8+T细胞对活化的PSCs具有更强的趋化能力，PSCs可分泌CXCL12。这些效应可被CXCL12基因敲除或全反式维甲酸处理PSCs所逆转。基于对人类PDAC样本和KPC小鼠的研究，激活的PSCs似乎可以减少CD8+T细胞向瘤旁间质的迁移，防止它们接触癌细胞。活化的PSCs失控信号可以阻止有效的抗肿瘤免疫反应。
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells. We used tissue microarray analysis to compare immune cell infiltration of different pancreatico-biliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis), and juxtatumoral stromal (<100 μm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice, and the effects of all-trans retinoic acid (ATRA) on these processes. Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase+ and CD68+ cells, compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8+, FoxP3+, CD56+, or CD20+ cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8+ T-cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8+ T-cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8+ T-cells from PDAC patients had increased chemotaxis towards activated PSCs, which secrete CXCL12, compared with quiescent PSC or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA. Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8+ T-cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective anti-tumor immune response.
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影响因子：
29.4
作者：
Apte MV;Wilson JS;Lugea A;Pandol SJ
通讯作者：
Pandol SJ
DOI：
10.1038/nri3191
发表时间：
2012-03-22
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Restifo NP;Dudley ME;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
64.8
作者：
Matsushita, Hirokazu;Vesely, Matthew D.;Koboldt, Daniel C.;Rickert, Charles G.;Uppaluri, Ravindra;Magrini, Vincent J.;Arthur, Cora D.;White, J. Michael;Chen, Yee-Shiuan;Shea, Lauren K.;Hundal, Jasreet;Wendl, Michael C.;Demeter, Ryan;Wylie, Todd;Allison, James P.;Smyth, Mark J.;Old, Lloyd J.;Mardis, Elaine R.;Schreiber, Robert D.
通讯作者：
Schreiber, Robert D.
影响因子：
29.4
作者：
Froeling, Fieke E. M.;Feig, Christine;Kocher, Hemant M.
通讯作者：
Kocher, Hemant M.
影响因子：
24.5
作者：
Neesse, Albrecht;Michl, Patrick;Tuveson, David A.
通讯作者：
Tuveson, David A.