Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade.
Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade.
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人类前列腺肿瘤抗原特异性CD8+调节T细胞被CTLA-4或IL-35阻断抑制。
DOI：
10.4049/jimmunol.1201744
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发表时间：
2012-12-15
期刊：
影响因子：
--
通讯作者：
McNeel DG
中科院分区：
文献类型：
--
作者：
Olson BM;Jankowska-Gan E;Becker JT;Vignali DA;Burlingham WJ;McNeel DG
调节性T细胞通过限制先天和适应性抗肿瘤免疫的产生，在癌症的发生和进展中发挥重要作用。我们假设，除了天然CD4+CD25+ Tregs和髓源性抑制细胞外，肿瘤抗原特异性调节性T细胞也会干扰免疫治疗后的抗肿瘤免疫检测。利用前列腺酸磷酸酶（PAP）编码DNA疫苗免疫的前列腺癌患者样本和跨体延迟型超敏反应（tvDTH）试验，我们发现免疫后PAP特异性效应反应的检测被PAP特异性调节细胞的活性所阻止。这些调节细胞为CD8+CTLA-4+，阻断CTLA-4可减轻对它们的抑制，但阻断IL-10和TGF-β则不能。此外，在没有pap特异性效应反应的情况下，免疫前检测抗原特异性CD8+调节性T细胞。这些pap特异性CD8+CTLA-4+抑制T细胞表达IL-35，阻断CTLA-4后IL-35水平降低，抑制CTLA-4或IL-35均可逆转pap特异性抑制tvDTH反应。pap特异性CD8+CTLA-4+ T细胞也以依赖il -35、不依赖接触的方式抑制T细胞增殖。综上所述，这些发现表明一种新的CD8+CTLA-4+ il -35分泌肿瘤抗原特异性调节性T细胞群在一些前列腺癌患者中自发产生，在免疫过程中持续存在，并且可以通过il -35依赖机制阻止抗原特异性效应反应的检测。
Regulatory T cells play important roles in cancer development and progression by limiting the generation of innate and adaptive anti-tumor immunity. We hypothesized that in addition to natural CD4+CD25+ Tregs and myeloid-derived suppressor cells, tumor antigen-specific regulatory T cells interfere with the detection of anti-tumor immunity following immunotherapy. Using samples from prostate cancer patients immunized with a DNA vaccine encoding prostatic acid phosphatase (PAP) and a trans-vivo delayed type hypersensitivity (tvDTH) assay, we found that the detection of PAP-specific effector responses following immunization was prevented by the activity of PAP-specific regulatory cells. These regulatory cells were CD8+CTLA-4+, and their suppression was relieved by blockade of CTLA-4, but not IL-10 or TGF-β. Moreover, antigen-specific CD8+ regulatory T cells were detected prior to immunization in the absence of PAP-specific effector responses. These PAP-specific CD8+CTLA-4+ suppressor T cells expressed IL-35, which was decreased following blockade of CTLA-4, and inhibition of either CTLA-4 or IL-35 reversed PAP-specific suppression of tvDTH response. PAP-specific CD8+CTLA-4+ T cells also suppressed T-cell proliferation in an IL-35-dependent, contact-independent fashion. Taken together, these findings suggest a novel population of CD8+CTLA-4+ IL-35-secreting tumor antigen-specific regulatory T cells arise spontaneously in some prostate cancer patients, persist during immunization, and can prevent the detection of antigen-specific effector responses by an IL-35-dependent mechanism.
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影响因子：
11.2
作者：
Degl'Innocenti, Elena;Grioni, Matteo;Bellone, Matteo
通讯作者：
Bellone, Matteo
影响因子：
15.3
作者：
Cai, JC;Lee, J;Burlingham, WJ
通讯作者：
Burlingham, WJ
影响因子：
4.4
作者：
Derks, Richard A.;Jankowska-Gan, Ewa;Burlingham, William J.
通讯作者：
Burlingham, William J.
影响因子：
5.5
作者：
Gregor, PD;Wolchok, JD;Houghton, AN
通讯作者：
Houghton, AN
DOI：
10.4049/jimmunol.1100315
发表时间：
2011-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chaturvedi V;Collison LW;Guy CS;Workman CJ;Vignali DA
通讯作者：
Vignali DA