A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice.
A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice.
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DOI：
10.1053/j.gastro.2014.02.055
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发表时间：
2014-06
期刊：
影响因子：
29.4
通讯作者：
Jaffee EM
中科院分区：
文献类型：
--
作者：
Keenan BP;Saenger Y;Kafrouni MI;Leubner A;Lauer P;Maitra A;Rucki AA;Gunderson AJ;Coussens LM;Brockstedt DG;Dubensky TW Jr;Hassan R;Armstrong TD;Jaffee EM
癌前病变和早期肿瘤含有免疫抑制微环境，对癌症疫苗产生障碍。KrasG12D / +; Trp53R172H / +;Pdx-1-Cre （KPC）小鼠在胰腺组织中表达一种活化形式的Kras，可发展为胰腺上皮内肿瘤（PanIN），并发展为胰腺导管腺癌（PDA）。我们用这些小鼠来研究PDA的免疫抑制。免疫KPC和KrasG12D/+；Pdx-1-Cre小鼠与细胞内单核增生李斯特菌（诱导CD4+和CD8+ t细胞免疫）工程化表达KrasG12D （LM-Kras）。该疫苗单独或与抗cd25抗体（PC61）和环磷酰胺一起接种，以消耗t -调节性（Treg）细胞。测量生存时间；收集胰腺和脾脏组织并进行组织学、流式细胞术和免疫组织化学分析。在KPC和KrasG12D/+中观察到干扰素γ介导的CD8+ t细胞应答；Pdx-1-Cre小鼠注射了LM-Kras，而未接种疫苗的小鼠则没有。与未接种疫苗的小鼠（中位生存期为150天，P = 0.002）、仅接种dm - kras的小鼠（中位生存期为150天，P = 0.050）和未接种Treg细胞的小鼠（中位生存期为170天，P = 0.048）相比，4-6周龄（具有早期PanINs）、Treg细胞缺失的KPC小鼠（中位生存期为170天，P = 0.048）相比，给予dm - kras显著延长了生存期并减少了PanIN进展（中位生存期为265天）。在8- 12周龄的小鼠（晚期PanIN）中，¼LM-Kras单独或与Treg细胞耗尽联合使用，都没有增加生存时间或减缓PanIN进展。LM-Kras联合Treg细胞耗损降低了胰腺淋巴结Foxp3+CD4+ T细胞的数量，增加了分泌白细胞介素17和干扰素g的CD4+ T细胞的数量，并导致胰腺CD11b+Gr1+细胞获得免疫刺激表型。用表达KrasG12D的单核细胞增生李斯特菌免疫KPC小鼠，与Treg细胞的消耗一起，减少了早期PanINs的进展，但没有减少晚期PanINs的进展。这种方法增加了炎症细胞的浸润。设计针对癌前胰腺病变的免疫疗法来减缓或阻止PDA的进展是可能的。
Premalignant lesions and early stage tumors contain immunosuppressive microenvironments that create barriers for cancer vaccines. KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) mice, which express an activated form of Kras in pancreatic tissues, develop pancreatic intraepithelial neoplasms (PanIN) that progress to pancreatic ductal adeno-carcinoma (PDA). We used these mice to study immune suppression in PDA. We immunized KPC and KrasG12D/+;Pdx-1-Cre mice with attenuated intracellular Listeria monocytogenes (which induces CD4+ and CD8+ T-cell immunity) engineered to express KrasG12D (LM-Kras). The vaccine was given alone or in sequence with an anti-CD25 antibody (PC61) and cyclophosphamide, to deplete T-regulatory (Treg) cells. Survival times were measured; pancreatic and spleen tissues were collected and analyzed by histologic, flow cytometry, and immunohistochemical analyses. Interferon γ-mediated, CD8+ T-cell responses were observed in KPC and KrasG12D/+;Pdx-1-Cre mice given LM-Kras, but not in unvaccinated mice. Administration of LM-Kras to KPC mice 4–6 weeks old (with early stage PanINs), depleted of Treg cells, significantly prolonged survival and reduced PanIN progression (median survival, 265 days), compared with unvaccinated mice (median survival, 150 days; P = .002), mice given only LM-Kras (median survival, 150 days; P = .050), and unvaccinated mice depleted of Treg cells (median (medium survival, 170 days; P = .048). In 8- to 12-week-old mice (with late-stage PanINs),¼LM-Kras, alone or in combination with Treg cell depletion, did not increase survival time or slow PanIN progression. The combination of LM-Kras and Treg cell depletion reduced numbers of Foxp3+CD4+ T cells in pancreatic lymph nodes, increased numbers of CD4+ T cells that secrete interleukin 17 and interferon g, and caused CD11b+Gr1+ cells in the pancreas to acquire an immunostimulatory phenotype. Immunization of KPC mice with Listeria monocytogenes engineered to express KrasG12D, along with depletion of Treg cells, reduces progression of early stage, but not late-stage, PanINs. This approach increases infiltration of the lesion with inflammatory cells. It might be possible to design immuno-therapies against premalignant pancreatic lesions to slow or prevent progression to PDA.
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影响因子：
15.9
作者：
Collins, Meredith A.;Bednar, Filip;di Magliano, Marina Pasca
通讯作者：
di Magliano, Marina Pasca
DOI：
10.1073/pnas.0406035101
发表时间：
2004-09-21
影响因子：
11.1
作者：
Brockstedt, DG;Giedlin, MA;Dubensky, TW
通讯作者：
Dubensky, TW
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
4.4
作者：
Liyanage, UK;Moore, TT;Linehan, DC
通讯作者：
Linehan, DC