Tolerization of tumor-specific T cells despite efficient initial priming in a primary murine model of prostate cancer
Tolerization of tumor-specific T cells despite efficient initial priming in a primary murine model of prostate cancer
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DOI：
10.4049/jimmunol.178.3.1268
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Hurwitz, Arthur A.
中科院分区：
文献类型：
--
作者：
Anderson, Michael J.;Shafer-Weaver, Kimberly;Hurwitz, Arthur A.
在本报告中，我们通过将肿瘤 Ag 特异性 T 细胞过继转移到荷有前列腺肿瘤的小鼠体内，研究了 T 细胞对前列腺癌 Ag 的反应。我们的研究结果表明，CD8(+) T 细胞最初在淋巴结中遇到肿瘤 Ag，并经历了失败的增殖反应。从肿瘤中分离出来后，残留的肿瘤特异性 T 细胞在功能上对肿瘤 Ag 具有耐受性，这通过它们无法脱颗粒和分泌 IFN-γ 和颗粒酶 B 来衡量。接下来，我们试图确定提供离体成熟的肽脉冲树突状细胞 (DC) 疫苗是否可以克服小鼠前列腺模型小鼠携带肿瘤的转基因腺癌的耐受机制。我们证明，在提供 DC 疫苗后，肿瘤 Ag 特异性 T 细胞受到保护而免受耐受。同时，前列腺肿瘤的大小也有所减小。然而，即使当激活的 DC 最初呈现肿瘤 Ag 时，持续存在于耐受性肿瘤环境中的 T 细胞也会逐渐失去 Ag 反应性。这些结果表明，尽管 DC 疫苗可以引发有效的抗肿瘤反应，但肿瘤产生的耐受环境仍然对 T 细胞产生抑制作用。此外，我们的结果表明，当试图引发有效的抗肿瘤免疫反应时，必须考虑两个障碍：为了维持肿瘤Ag反应性，T细胞必须有效地启动以克服以耐受方式呈现的肿瘤Ag，并免受肿瘤微环境的抑制机制的影响。
In this report, we studied T cell responses to a prostate cancer Ag by adoptively transferring tumor Ag-specific T cells into prostate tumor-bearing mice. Our findings demonstrate that CD8(+) T cells initially encountered tumor Ag in the lymph node and underwent an abortive proliferative response. Upon isolation from the tumor, the residual tumor-specific T cells were functionally tolerant of tumor Ag as measured by their inability to degranulate and secrete IFN-gamma and granzyme B. We next sought to determine whether providing an ex vivo-matured, peptide-pulsed dendritic cell (DC) vaccine could overcome the tolerizing mechanisms of tumor-bearing transgenic adenocarcinoma of the mouse prostate model mice. We demonstrate that tumor Ag-specific T cells were protected from tolerance following provision of the DC vaccine. Concurrently, there was a reduction in prostate tumor size. However, even when activated DCs initially present tumor Ag, T cells persisting within the tolerogenic tumor environment gradually lost Ag reactivity. These results suggest that even though a productive antitumor response can be initiated by a DC vaccine, the tolerizing environment created by the tumor still exerts suppressive effects on the T cells. Furthermore, our results demonstrate that when trying to elicit an effective antitumor immune response, two obstacles must be considered: to maintain tumor Ag responsiveness, T cells must be efficiently primed to overcome tumor Ag presented in a tolerizing manner and protected from the suppressive mechanisms of the tumor microenvironment.