Exclusion of T Cells From Pancreatic Carcinomas in Mice Is Regulated by Ly6C(low) F4/80(+) Extratumoral Macrophages.
Exclusion of T Cells From Pancreatic Carcinomas in Mice Is Regulated by Ly6C(low) F4/80(+) Extratumoral Macrophages.
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DOI：
10.1053/j.gastro.2015.04.010
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发表时间：
2015-07
期刊：
影响因子：
29.4
通讯作者：
Vonderheide RH
中科院分区：
文献类型：
--
作者：
Beatty GL;Winograd R;Evans RA;Long KB;Luque SL;Lee JW;Clendenin C;Gladney WL;Knoblock DM;Guirnalda PD;Vonderheide RH
诱导T细胞反应的免疫疗法已经在患者和小鼠身上显示出对一些实体恶性肿瘤的疗效，但对胰腺导管腺癌(PDAC)几乎没有效果。我们研究了PDAC逃避免疫疗法诱导的T细胞反应的能力是由于肿瘤细胞的低免疫原性水平，还是肿瘤的免疫抑制机制，或者两者兼而有之。KrasG12D/+、Trp53R172H/+、PDX-1-Cre(KPC)小鼠或其仔鼠(对照组)皮下注射同基因KPC来源的PDAC细胞系。然后给予小鼠吉西他滨和CD40激动剂，以诱导T细胞介导的肿瘤特异性免疫。一些小鼠也被给予氯屈膦酸盐脂质体来耗尽巨噬细胞。监测肿瘤生长情况。收集肿瘤和脾组织，进行组织学、流式细胞术和免疫组织化学分析。吉西他滨联合CD40激动剂可诱导KPC和对照组小鼠皮下PDAC的T细胞依赖性消退。在给予吉西他滨和CD40激动剂的KPC小鼠中，CD4+和CD8+T细胞渗入皮下肿瘤，但只有CD4+T细胞渗入自发性胰腺肿瘤(不包括CD8+T细胞)。在Ly6Clow F4/80+肿瘤外巨噬细胞缺失的小鼠中，吉西他滨与CD40激动剂联合应用可刺激CD8+T细胞对自发肿瘤的侵袭，并由CD8+T细胞介导的肿瘤消退。居住在肿瘤微环境外的Ly6Clow F4/80+巨噬细胞调节T细胞向PDAC的渗透，并建立免疫豁免部位。逆转由肿瘤外巨噬细胞调节的PDAC免疫豁免权的策略可能会提高PDAC患者的T细胞免疫治疗效果。
Immunotherapies that induce T-cell responses have shown efficacy against some solid malignancies in patients and mice, but these have little effect on pancreatic ductal adenocarcinoma (PDAC). We investigated whether the ability of PDAC to evade T-cell responses induced by immunotherapies results from the low level of immunogenicity of tumor cells, the tumor's immunosuppressive mechanisms, or both. KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mice, which develop spontaneous PDAC, or their littermates (controls) were given subcutaneous injections of a syngeneic KPC-derived PDAC cell line. Mice were then given gemcitabine and an agonist of CD40 to induce tumor-specific immunity mediated by T cells. Some mice were also given clodronate-encapsulated liposomes to deplete macrophages. Tumor growth was monitored. Tumor and spleen tissues were collected and analyzed by histology, flow cytometry, and immunohistochemistry. Gemcitabine in combination with a CD40 agonist induced T cell-dependent regression of subcutaneous PDAC in KPC and control mice. In KPC mice given gemcitabine and a CD40 agonist, CD4+ and CD8+ T cells infiltrated subcutaneous tumors, but only CD4+ T cells infiltrated spontaneous pancreatic tumors (not CD8+ T cells). In mice depleted of Ly6Clow F4/80+ extra-tumor macrophages, the combination of gemcitabine and a CD40 agonist stimulated infiltration of spontaneous tumors by CD8+ T cells and induced tumor regression, mediated by CD8+ T cells. Ly6Clow F4/80+ macrophages that reside outside of the tumor microenvironment regulate infiltration of T cells into PDAC and establish a site of immune privilege. Strategies to reverse the immune privilege of PDAC, which is regulated by extra-tumor macrophages, might increase the efficacy of T cell immunotherapy for patients with PDAC.
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单核细胞CCR2（+）髓样衍生的抑制细胞通过将活化的CD8 T细胞浸润限制在肿瘤微环境中，从而促进免疫逃逸。
影响因子：
11.2
作者：
Lesokhin AM;Hohl TM;Kitano S;Cortez C;Hirschhorn-Cymerman D;Avogadri F;Rizzuto GA;Lazarus JJ;Pamer EG;Houghton AN;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
17.1
作者：
Highfill SL;Cui Y;Giles AJ;Smith JP;Zhang H;Morse E;Kaplan RN;Mackall CL
通讯作者：
Mackall CL
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.
肿瘤相关巨噬细胞的细胞和分子起源。
DOI：
10.1126/science.1252510
发表时间：
2014-05-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franklin RA;Liao W;Sarkar A;Kim MV;Bivona MR;Liu K;Pamer EG;Li MO
通讯作者：
Li MO
影响因子：
64.8
作者：
Ridge, JP;Di Rosa, F;Matzinger, P
通讯作者：
Matzinger, P