NFκB in Pancreatic Stellate Cells Reduces Infiltration of Tumors by Cytotoxic T Cells and Killing of Cancer Cells, via Up-regulation of CXCL12.
NFκB in Pancreatic Stellate Cells Reduces Infiltration of Tumors by Cytotoxic T Cells and Killing of Cancer Cells, via Up-regulation of CXCL12.
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DOI：
10.1053/j.gastro.2018.05.051
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发表时间：
2018-09
期刊：
影响因子：
29.4
通讯作者：
Dudeja V
中科院分区：
文献类型：
--
作者：
Garg B;Giri B;Modi S;Sethi V;Castro I;Umland O;Ban Y;Lavania S;Dawra R;Banerjee S;Vickers S;Merchant NB;Chen SX;Gilboa E;Ramakrishnan S;Saluja A;Dudeja V
免疫疗法对胰腺癌无效。我们研究了胰腺基质细胞中核因子κB的活性是否有助于抑制抗肿瘤免疫反应的环境。将KrasG12D/+、Trp53 R172H/+、Pdx-1cre(Kpc)胰腺癌细胞和从C57BL/6(对照组)或编码NFkBp50亚单位基因缺失的小鼠(Nfkb1或p50−/−小鼠)中提取的胰腺星状细胞(PSCs)联合注射给C57BL/6或RAG1−/−小鼠的胰腺组织。以肿瘤生长为终点进行测量。其他小鼠则被注射LLC肺癌细胞或B16-F10黑色素瘤细胞与对照组或p50−/−成纤维细胞。用CD8抗体去除C57BL/6小鼠体内的细胞毒性T细胞，并检测有无对照或p50−/−PSCs的KPC细胞对肿瘤生长的影响。部分小鼠给予CXCL12(AMD3100)抑制剂，观察肿瘤生长情况。用Boyden小室实验测定T细胞向癌细胞的迁移。联合注射KPC细胞(或LLC或B16-F10细胞)和p50−/−PSCs的C57BL/6小鼠比注射癌细胞和对照PSCs的小鼠产生更小的肿瘤。与与对照PSC一起注射KPC细胞形成的肿瘤相比，当KPC细胞与p50−/−PSCs一起注射时，激活的细胞毒性T细胞的侵袭增加，而CXCL12水平降低。当C57BL/6小鼠或Rag1−/−−/−小鼠的CD8+T细胞被去除时，KPC细胞与对照组或p50 CD8+PSCs共注射时产生相同大小的肿瘤。CXCL12抑制剂延缓了肿瘤的生长，增加了细胞毒性T细胞对肿瘤的侵袭。在体外，PSCs表达p50减少了T细胞向癌细胞的迁移和杀伤。当与癌细胞一起培养时，对照组PSC表达的CXCL12水平是p50−/−PSCs的10倍。CXCL12抑制剂在培养中增加了T细胞向KPC细胞的迁移。在对小鼠和细胞系的研究中，我们发现PSCs中的NFκB活性通过增加CXCL12的表达来促进肿瘤生长，CXCL12可以阻止细胞毒性T细胞渗透到肿瘤中并杀死癌细胞。阻断胰腺肿瘤细胞中CXCL12的策略可能会增强抗肿瘤免疫。
Immunotherapies are ineffective against pancreatic cancer. We investigated whether the activity of nuclear factor (NF)κB in pancreatic stromal cells contributes to an environment that suppresses anti-tumor immune response. Pancreata of C57BL/6 or Rag1−/− mice were given pancreatic injections of a combination of KrasG12D/+; Trp53 R172H/+; Pdx-1cre (KPC) pancreatic cancer cells and pancreatic stellate cells (PSCs) extracted from C57BL/6 (control) or mice with disruption of the gene encoding the NFkB p50 subunit (Nfkb1 or p50−/− mice). Tumor growth was measured as an endpoint. Other mice were given injections of LLC lung cancer cells or B16-F10 melanoma cells with control or p50−/− fibroblasts. Cytotoxic T cells were depleted from C57BL/6 mice by administration of antibodies against CD8 (anti-CD8), and growth of tumors from KPC cells, with or without control or p50−/− PSCs, was measured. Some mice were given an inhibitor of CXCL12 (AMD3100) and tumor growth was measured. T-cell migration toward cancer cells was measured using the Boyden chamber assay. C57BL/6 mice co-injected with KPC cells (or LLC or B16-F10 cells) and p50−/− PSCs developed smaller tumors than mice given injections of the cancer cells along with control PSCs. Tumors that formed when KPC cells were injected along with p50−/− PSCs had increased infiltration by activated cytotoxic T cells along with decreased levels of CXCL12, compared to tumors grown from KPC cells injected along with control PSCs. KPC cells, when co-injected with control or p50−/− PSCs, developed the same size tumors when CD8+ T cells were depleted from C57BL/6 mice or in Rag1−/− mice. The CXCL12 inhibitor slowed tumor growth and increased tumor infiltration by cytotoxic T cells. In vitro expression of p50 by PSCs reduced T-cell migration toward and killing of cancer cells. When cultured with cancer cells, control PSCs expressed 10-fold higher levels of CXCL12 than p50−/− PSCs. The CXCL12 inhibitor increased migration of T cells toward KPC cells in culture. In studies of mice and cell lines, we found that NFκB activity in PSCs promotes tumor growth by increasing expression of CXCL12, which prevents cytotoxic T cells from infiltrating the tumor and killing cancer cells. Strategies to block CXCL12 in pancreatic tumor cells might increase anti-tumor immunity.
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影响因子：
50.3
作者：
Lee KE;Bar-Sagi D
通讯作者：
Bar-Sagi D
DOI：
10.1073/pnas.1320318110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Feig, Christine;Jones, James O.;Fearon, Douglas T.
通讯作者：
Fearon, Douglas T.
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
11.5
作者：
Teicher, Beverly A.;Fricker, Simon P.
通讯作者：
Fricker, Simon P.
影响因子：
8.8
作者：
KAPLAN, HS
通讯作者：
KAPLAN, HS