Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive T cell therapy in a murine model of melanoma.
Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive T cell therapy in a murine model of melanoma.
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DOI：
10.4049/jimmunol.1200274
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发表时间：
2012-12-01
期刊：
影响因子：
--
通讯作者：
Pilon-Thomas S
中科院分区：
文献类型：
--
作者：
Kodumudi KN;Weber A;Sarnaik AA;Pilon-Thomas S
在过继性转移肿瘤特异性T细胞之前，给予非清髓性化疗药物或全身照射（TBI）可能会减少或消除免疫抑制群体，如T调节细胞（Tregs）和髓源性抑制细胞（MDSC）。在免疫重建期间，对这些群体知之甚少。本研究旨在了解黑色素瘤荷瘤小鼠TBI后这些群体的重建率和功能。测定B16黑色素瘤荷瘤小鼠tbi诱导淋巴细胞减少后CD4+CD25+Foxp3+ Tregs和CD11b+Gr1+ MDSC的重建率和抑制活性。为了消除抑制群体的快速重建，我们用多西他赛（DTX）治疗小鼠，一种已知的靶向MDSC的化疗药物，结合过继T细胞转移和DC免疫治疗。Treg和MDSC群体在tbi诱导的淋巴细胞减少后都表现出快速的重建。虽然重组的Tregs与来自未治疗小鼠的Tregs一样具有抑制作用，但与来自荷瘤小鼠的内源性MDSC相比，MDSC对CD8+ T细胞增殖的抑制活性增强。tbi诱导的淋巴细胞减少后，DTX治疗提高了黑色素瘤小鼠过继性T细胞转移和DC免疫治疗的疗效，诱导肿瘤生长显著降低，提高生存率。肿瘤消退与CTL活性的增加和过继转移T细胞的持久性相关。总的来说，这些发现表明，tbi诱导的MDSC具有高度的免疫抑制作用，阻断它们的快速重建可能会提高疫苗接种策略和过继免疫治疗的效果。
Administration of non-myeloablative chemotherapeutic agents or total body irradiation (TBI) prior to adoptive transfer of tumor-specific T cells may reduce or eliminate immunosuppressive populations such as T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSC). Little is known about these populations during immune reconstitution. This study was designed to understand the reconstitution rate and function of these populations post TBI in melanoma tumor bearing mice. Reconstitution rate and suppressive activity of CD4+CD25+Foxp3+ Tregs and CD11b+Gr1+ MDSC following TBI-induced lymphopenia was measured in B16 melanoma tumor-bearing mice. In order to ablate the rapid reconstitution of suppressive populations, we treated mice with docetaxel (DTX), a known chemotherapeutic agent that targets MDSC, in combination with adoptive T cell transfer and DC immunotherapy. Both Treg and MDSC populations exhibited rapid reconstitution after TBI-induced lymphopenia. While reconstituted Tregs were just as suppressive as Tregs from untreated mice, MDSC demonstrated enhanced suppressive activity of CD8+ T cell proliferation compared to endogenous MDSC from tumor bearing mice. TBI-induced lymphopenia followed by DTX treatment improved the efficacy of adoptive T cell transfer and DC immunotherapy in melanoma-bearing mice, inducing a significant reduction in tumor growth and enhancing survival. Tumor regression correlated with increased CTL activity and persistence of adoptively transferred T cells. Overall, these findings suggest that TBI-induced MDSC are highly immunosuppressive and blocking their rapid reconstitution may improve the efficacy of vaccination strategies and adoptive immunotherapy.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
通过淋巴结消除来清除稳态细胞因子下沉，增强了采用转移的肿瘤特异性CD8+ T细胞的功效。
影响因子：
15.3
作者：
Gattinoni, Luca;Finkelstein, Steven E;Klebanoff, Christopher A;Antony, Paul A;Palmer, Douglas C;Spiess, Paul J;Hwang, Leroy N;Yu, Zhiya;Wrzesinski, Claudia;Heimann, David M;Surh, Charles D;Rosenberg, Steven A;Restifo, Nicholas P
通讯作者：
Restifo, Nicholas P
影响因子：
11.5
作者：
Kline, Justin;Brown, Ian E.;Gajewski, Thomas F.
通讯作者：
Gajewski, Thomas F.
影响因子：
4.4
作者：
Almand, B;Clark, JI;Gabrilovich, DI
通讯作者：
Gabrilovich, DI
影响因子：
45.3
作者：
Dudley, ME;Wunderlich, JR;Rosenberg, SA
通讯作者：
Rosenberg, SA