Possible role of arginase-1 in concomitant tumor immunity.
Possible role of arginase-1 in concomitant tumor immunity.
复制标题
精氨酸酶-1在伴有肿瘤免疫中的可能作用。
DOI：
10.1371/journal.pone.0091370
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Routes JM
中科院分区：
文献类型：
--
作者：
Korrer MJ;Zhang Y;Routes JM
腺病毒血清型2或血清型5（Ad 2/5）E1 A在肿瘤细胞中的表达通过增强NK细胞介导的和T细胞介导的抗肿瘤免疫应答（与E1 A结合p300的能力相关的活性）来降低其体内致瘤性。我们确定E1 A是否可以用作分子佐剂来增强对模型肿瘤抗原卵清蛋白（OVA）的抗原特异性T细胞应答。为了实现这一目标，我们在B6衍生的高度致瘤性MCA-205肿瘤细胞系中稳定表达了E1 A和OVA的融合蛋白（MCA-205-E1 A-OVA）、OVA（MCA-205-OVA）或不能结合p300和OVA的E1 A突变体（E1 A-Δp300-OVA）。在B6小鼠中，MCA-205-E1 A-OVA肿瘤细胞的致瘤性比MCA-205-OVA、MCA-205-E1 A-Δp300-OVA或MCA-205低10，000倍以上。然而，用活MCA-205-OVA、MCA-205-E1 A-Δp300-OVA和MCA-E1 A-OVA肿瘤细胞免疫B6小鼠诱导了几乎相等的OVA特异性CD 4 T细胞和CD 8 CTL应答。进一步的研究表明，一侧腹患有原发性、扩大的MCA-205-OVA或MCA-205-E1 A-Δp300-OVA肿瘤的小鼠表现出UVA特异性抗肿瘤T细胞反应，该反应拒绝对侧腹的致瘤剂量的MCA-205-OVA细胞（伴随肿瘤免疫）。接下来，我们发现在进行性MCA-205-OVA肿瘤中的肿瘤相关巨噬细胞（TAM），但不是表达高水平的抗肿瘤酶-1的MCA-205-E1 A-OVA肿瘤，已知抗肿瘤酶-1具有局部免疫抑制活性。总之，用表达OVA、E1 A-Δp300-OVA或E1 A-OVA的MCA-205细胞免疫小鼠诱导了等效的OVA特异性CD 4和CD 8抗肿瘤应答。在MCA-205-OVA中发现的TAM，而不是MCA-205-E1 A-OVA，肿瘤表达高水平的腺苷酸酶-1。我们假设MCA-205-OVA或MCA-205-E1 A-Δp300-OVA肿瘤细胞中TAM产生的抗肿瘤酶-1导致肿瘤微环境中无效的抗肿瘤免疫应答，但不会导致全身抗肿瘤免疫的抑制。
The expression of Adenovirus serotype 2 or serotype 5 (Ad2/5) E1A in tumor cells reduces their tumorigenicity in vivo by enhancing the NK cell mediated and T cell mediated anti-tumor immune response, an activity that correlates with the ability of E1A to bind p300. We determined if E1A could be used as a molecular adjuvant to enhance antigen-specific T cell responses to a model tumor antigen, ovalbumin (OVA). To achieve this goal, we stably expressed a fusion protein of E1A and OVA (MCA-205-E1A-OVA), OVA (MCA-205-OVA) or a mutant version of E1A unable to bind p300 and OVA (E1A-Δp300-OVA) in the B6-derived, highly tumorigenic MCA-205 tumor cell line. MCA-205-E1A-OVA tumor cells were over 10,000 fold less tumorigenic than MCA-205-OVA, MCA-205-E1A-Δp300-OVA, or MCA-205 in B6 mice. However, immunization of B6 mice with live MCA-205-OVA, MCA-205-E1A-Δp300-OVA and MCA-E1A-OVA tumor cells induced nearly equivalent OVA-specific CD4 T cells and CD8 CTL responses. Further studies revealed that mice with primary, enlarging MCA-205-OVA or MCA-205-E1A-Δp300-OVA tumors on one flank exhibited OVA-specific anti-tumor T cell responses that rejected a tumorigenic dose of MCA-205-OVA cells on the contralateral flank (concomitant tumor immunity). Next we found that tumor associated macrophages (TAMs) in progressive MCA-205-OVA tumors, but not MCA-205-E1A-OVA tumors that expressed high levels of arginase-1, which is known to have local immunosuppressive activities. In summary, immunization of mice with MCA-205 cells expressing OVA, E1A-Δp300-OVA or E1A-OVA induced equivalent OVA-specific CD4 and CD8 anti-tumor responses. TAMs found in MCA-205-OVA, but not MCA-205-E1A-OVA, tumors expressed high levels of arginase-1. We hypothesize that the production of arginase-1 by TAMs in MCA-205-OVA or MCA-205-E1A-Δp300-OVA tumor cells leads to an ineffective anti-tumor immune response in the tumor microenvironment, but does not result in inhibition of a systemic anti-tumor immunity.
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影响因子：
5.3
作者：
Iyer, RK;Yoo, PK;Cederbaum, SD
通讯作者：
Cederbaum, SD
DOI：
10.1084/jem.176.1.287
发表时间：
1992-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Stein M;Keshav S;Harris N;Gordon S
通讯作者：
Gordon S
影响因子：
4.4
作者：
Routes, JM;Ryan, S;Cook, JL
通讯作者：
Cook, JL
DOI：
10.1073/pnas.83.18.6965
发表时间：
1986-09-01
影响因子：
11.1
作者：
COOK, JL;WALKER, TA;PILDER, SH
通讯作者：
PILDER, SH
影响因子：
56.9
作者：
COOK, JL;LEWIS, AM
通讯作者：
LEWIS, AM