Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity.
Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity.
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DOI：
10.1136/gutjnl-2013-306271
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发表时间：
2014-11
期刊：
影响因子：
24.5
通讯作者：
Hingorani SR
中科院分区：
文献类型：
--
作者：
Stromnes IM;Brockenbrough JS;Izeradjene K;Carlson MA;Cuevas C;Simmons RM;Greenberg PD;Hingorani SR
胰腺导管腺癌（PDA）的特征是强烈的结缔组织增生，包括免疫抑制细胞的显著积累，这些细胞可以保护肿瘤细胞免受免疫检测。如果恶性细胞不能表达高水平的抗原，这些抗原具有足够的免疫原性，从而产生效应T细胞反应，免疫逃避可能会进一步增强。在本报告中，我们研究了免疫抑制癌症条件的骨髓细胞的主要亚群，这些细胞记录和塑造了胰腺癌的进展。我们发现，在一个原生的、基因工程的PDA小鼠模型（GEMM）中，选择性地消耗一个骨髓源性抑制细胞（MDSC）亚群，揭示了适应性免疫反应参与和靶向肿瘤上皮细胞的能力。结合体内和体外研究进行了采用GEMM，忠实地概括了人类PDA的主要特征。主要的癌症条件骨髓细胞亚群在体内被特异性靶向，并确定了生物学结果。PDA通过产生已知的影响骨髓生成的因子，协调诱导不同的癌症相关骨髓细胞亚群。这些未成熟的骨髓细胞抑制活化T细胞的增殖并诱导凋亡。自体PDA中粒细胞MDSC （Gr-MDSC）的靶向消耗增加了活化CD8 T细胞的瘤内积聚和肿瘤上皮细胞的凋亡，并重塑了肿瘤间质。胰腺的肿瘤导管细胞诱导不同的髓细胞亚群，促进肿瘤细胞的存活和积累。靶向清除单个髓细胞亚群，即Gr-MDSC，可以揭示内源性T细胞反应，揭示意想不到的潜在免疫，并调用靶向Gr-MDSC作为治疗这种高致命性疾病的潜在策略。
Pancreatic ductal adenocarcinoma (PDA) is characterized by a robust desmoplasia, including the notable accumulation of immunosuppressive cells that shield neoplastic cells from immune detection. Immune evasion may be further enhanced if the malignant cells fail to express high levels of antigens that are sufficiently immunogenic to engender an effector T cell response. In this report, we investigate the predominant subsets of immunosuppressive cancer-conditioned myeloid cells that chronicle and shape pancreas cancer progression. We show that selective depletion of one subset of myeloid-derived suppressor cells (MDSC) in an autochthonous, genetically engineered mouse model (GEMM) of PDA unmasks the ability of the adaptive immune response to engage and target tumor epithelial cells. A combination of in vivo and in vitro studies were performed employing a GEMM that faithfully recapitulates the cardinal features of human PDA. The predominant cancer-conditioned myeloid cell subpopulation was specifically targeted in vivo and the biological outcomes determined. PDA orchestrates the induction of distinct subsets of cancer-associated myeloid cells through the production of factors known to influence myelopoeisis. These immature myeloid cells inhibit the proliferation and induce apoptosis of activated T cells. Targeted depletion of granulocytic MDSC (Gr-MDSC) in autochthonous PDA increases the intratumoral accumulation of activated CD8 T cells and apoptosis of tumor epithelial cells, and also remodels the tumor stroma. Neoplastic ductal cells of the pancreas induce distinct myeloid cell subsets that promote tumor cell survival and accumulation. Targeted depletion of a single myeloid subset, the Gr-MDSC, can unmask an endogenous T cell response, revealing an unexpected latent immunity and invoking targeting of Gr-MDSC as a potential strategy to exploit for treating this highly lethal disease.
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影响因子：
3.7
作者：
Fridlender ZG;Sun J;Mishalian I;Singhal S;Cheng G;Kapoor V;Horng W;Fridlender G;Bayuh R;Worthen GS;Albelda SM
通讯作者：
Albelda SM
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影响因子：
64.8
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Biankin, Andrew V.;Waddell, Nicola;Kassahn, Karin S.;Gingras, Marie-Claude;Muthuswamy, Lakshmi B.;Johns, Amber L.;Miller, David K.;Wilson, Peter J.;Patch, Ann-Marie;Wu, Jianmin;Chang, David K.;Cowley, Mark J.;Gardiner, Brooke B.;Song, Sarah;Harliwong, Ivon;Idrisoglu, Senel;Nourse, Craig;Nourbakhsh, Ehsan;Manning, Suzanne;Wani, Shivangi;Gongora, Milena;Pajic, Marina;Scarlett, Christopher J.;Gill, Anthony J.;Pinho, Andreia V.;Rooman, Ilse;Anderson, Matthew;Holmes, Oliver;Leonard, Conrad;Taylor, Darrin;Wood, Scott;Xu, Qinying;Nones, Katia;Fink, J. Lynn;Christ, Angelika;Bruxner, Tim;Cloonan, Nicole;Kolle, Gabriel;Newell, Felicity;Pinese, Mark;Mead, R. Scott;Humphris, Jeremy L.;Kaplan, Warren;Jones, Marc D.;Colvin, Emily K.;Nagrial, Adnan M.;Humphrey, Emily S.;Chou, Angela;Chin, Venessa T.;Chantrill, Lorraine A.;Mawson, Amanda;Samra, Jaswinder S.;Kench, James G.;Lovell, Jessica A.;Daly, Roger J.;Merrett, Neil D.;Toon, Christopher;Epari, Krishna;Nguyen, Nam Q.;Barbour, Andrew;Zeps, Nikolajs;Kakkar, Nipun;Zhao, Fengmei;Wu, Yuan Qing;Wang, Min;Muzny, Donna M.;Fisher, William E.;Brunicardi, F. Charles;Hodges, Sally E.;Reid, Jeffrey G.;Drummond, Jennifer;Chang, Kyle;Han, Yi;Lewis, Lora R.;Dinh, Huyen;Buhay, Christian J.;Beck, Timothy;Timms, Lee;Sam, Michelle;Begley, Kimberly;Brown, Andrew;Pai, Deepa;Panchal, Ami;Buchner, Nicholas;De Borja, Richard;Denroche, Robert E.;Yung, Christina K.;Serra, Stefano;Onetto, Nicole;Mukhopadhyay, Debabrata;Tsao, Ming-Sound;Shaw, Patricia A.;Petersen, Gloria M.;Gallinger, Steven;Hruban, Ralph H.;Maitra, Anirban;Iacobuzio-Donahue, Christine A.;Schulick, Richard D.;Wolfgang, Christopher L.;Morgan, Richard A.;Lawlor, Rita T.;Capelli, Paola;Corbo, Vincenzo;Scardoni, Maria;Tortora, Giampaolo;Tempero, Margaret A.;Mann, Karen M.;Jenkins, Nancy A.;Perez-Mancera, Pedro A.;Adams, David J.;Largaespada, David A.;Wessels, Lodewyk F. A.;Rust, Alistair G.;Stein, Lincoln D.;Tuveson, David A.;Copeland, Neal G.;Musgrove, Elizabeth A.;Scarpa, Aldo;Eshleman, James R.;Hudson, Thomas J.;Sutherland, Robert L.;Wheeler, David A.;Pearson, John V.;McPherson, John D.;Gibbs, Richard A.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.
影响因子：
24.5
作者：
Jacobetz MA;Chan DS;Neesse A;Bapiro TE;Cook N;Frese KK;Feig C;Nakagawa T;Caldwell ME;Zecchini HI;Lolkema MP;Jiang P;Kultti A;Thompson CB;Maneval DC;Jodrell DI;Frost GI;Shepard HM;Skepper JN;Tuveson DA
通讯作者：
Tuveson DA