Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C).
Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C).
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DOI：
10.4049/jimmunol.0801829
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发表时间：
2009-02-15
期刊：
影响因子：
--
通讯作者：
Cole DJ
中科院分区：
文献类型：
--
作者：
Salem ML;Díaz-Montero CM;Al-Khami AA;El-Naggar SA;Naga O;Montero AJ;Khafagy A;Cole DJ
最近的临床前研究表明，将CD8+T细胞过继转移到淋巴细胞减少的宿主体内后接种疫苗可以增强转移细胞的治疗抗肿瘤反应。然而，淋巴减少微环境有利于抗原特异性CD8+T细胞反应的机制仍然不清楚。我们在此表明，在环磷酰胺(CTX)治疗后8-16天(称为恢复期)，单用4 mg环磷酰胺(CTX)可诱导外周血中未成熟树突状细胞(DC)显著扩张。在体外，这些DC是有功能的，因为它们在激活后表现出正常的吞噬能力和有效的抗原提呈能力。在体内，在DC扩张高峰期(淋巴细胞减少后第12天)给予TLR3激动剂Poly(I：C)可诱导炎性细胞因子的产生，并增加淋巴结中激活的DC的数量。重要的是，gp10025-33黑色素瘤多肽联合Poly(I：C)在以相同方案初始启动后12天增强显著增加过继转移的PMEL-1 CD8+T细胞的扩增和抗肿瘤效果。在抗原增强过程中耗尽激活的DC后，这些反应被取消。综上所述，我们的数据表明，在恢复阶段，CTX治疗可以诱导未成熟DC的扩张，这些DC具有功能，可以在体内利用，以培养更有效的抗肿瘤过继免疫治疗策略。
Recent preclinical studies suggest that vaccination following adoptive transfer of CD8+ T cells into a lymphopenic host can augment the therapeutic antitumor responses of the transferred cells. However, the mechanism by which the lymphopenic microenvironment benefits Ag-specific CD8+ T cell responses remains elusive. We show herein that induction of lymphodepletion by a single 4 mg cyclophosphamide (CTX) treatment induces a marked expansion of immature dendritic cells (DCs) in the peripheral blood on days 8–16 post-CTX (termed restoration phase). In vitro, these DCs were functional, because they showed normal phagocytosis and effective Ag presentation capability upon activation. In vivo, administration of the TLR3 agonist poly(I:C) at the peak of DC expansion (day 12 postlymphopenia) induced inflammatory cytokine production and increases in the number of activated DCs in lymph nodes. Importantly, boosting with gp10025–33 melanoma peptide combined with poly(I:C) 12 days after an initial priming with the same regimen significantly increased the expansion and the antitumor efficacy of adoptively transferred pmel-1 CD8+ T cells. These responses were abrogated after depletion of activated DCs during Ag boosting. In conclusion, our data show that CTX treatment induces, during the restoration phase, expansion of immature DCs, which are functional and can be exploited in vivo to foster more effective antitumor adoptive immunotherapy strategies.
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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：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
DOI：
10.1073/pnas.0503726102
发表时间：
2005-07-05
影响因子：
11.1
作者：
Klebanoff, CA;Gattinoni, L;Restifo, NP
通讯作者：
Restifo, NP
影响因子：
30.5
作者：
Liu, Kang;Waskow, Claudia;Nussenzweig, Michel
通讯作者：
Nussenzweig, Michel
影响因子：
2.8
作者：
Adachi, Y;Toki, J;Ikehara, S
通讯作者：
Ikehara, S