Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling

被引:438
作者
Paulos, Chrystal M.
Wrzesinski, Claudia
Kaiser, Andrew
Hinrichs, Christian S.
Chieppa, Marcello
Cassard, Lydie
Palmer, Douglas C.
Boni, Andrea
Muranski, Pawel
Yu, Zhiya
Gattinoni, Luca
Antony, Paul A.
Rosenberg, Steven A.
Restifo, Nicholas P.
机构
[1] NCI, NIH, Hatfield Marine Sci Ctr, Bethesda, MD 20892 USA
[2] NIAID, NIH, Bethesda, MD 20892 USA
[3] Johns Hopkins Univ, Baltimore, MD USA
关键词
D O I
10.1172/JCI32205
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Lymphodepletion with total body irradiation (TBI) increases the efficacy of adoptively transferred tumor-specific CD8(+) T cells by depleting inhibitory lymphocytes and increasing homeostatic cyrokine levels. We found that TBI augmented the function of adoptively transferred CD8(+)T cells in mice genetically deficient in an lymphocytes, indicating the existence of another TBI mechanism of action. Additional investigation revealed commensal gut microflora in the mesenteric lymph nodes and elevated LPS levels in the sera of irradiated mice. These findings correlated with increased dendritic cell activation and heightened levels of systemic inflammatory cytokines. Reduction of host microflora using antibiotics, neutralization of serum LPS using polymyxin B, or removal of LPS signaling components using mice genetically deficient in CD14 and TLR4 reduced the beneficial effects of TBI on tumor regression. Conversely, administration of microbial ligand-containing serum or ultrapure LPS from irradiated animals to nonirradiated antibody-lymphodepleted mice enhanced CD8(+)T cell activation and improved tumor regression. Administration of ultrapure LPS to irradiated animals further enhanced the number and function of the adoptively transferred cells, leading to long-term cure of mice with large B16F10 tumors and enhanced autoimmune vitiligo. Thus, disruption of the homeostatic balance between the host and microbes can enhance cell-based tumor immunotherapy.
引用
收藏
页码:2197 / 2204
页数:8
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