Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling
Chrystal M. Paulos, … , Steven A. Rosenberg, Nicholas P. Restifo
Chrystal M. Paulos, … , Steven A. Rosenberg, Nicholas P. Restifo
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2197-2204. https://doi.org/10.1172/JCI32205.
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Research Article Oncology

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

Abstract

Lymphodepletion with total body irradiation (TBI) increases the efficacy of adoptively transferred tumor-specific CD8+ T cells by depleting inhibitory lymphocytes and increasing homeostatic cytokine levels. We found that TBI augmented the function of adoptively transferred CD8+ T cells in mice genetically deficient in all 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.

Authors

Chrystal M. Paulos, Claudia Wrzesinski, Andrew Kaiser,, Christian S. Hinrichs, Marcello Chieppa, Lydie Cassard, Douglas C. Palmer, Andrea Boni, Pawel Muranski, Zhiya Yu, Luca Gattinoni, Paul A. Antony, Steven A. Rosenberg, Nicholas P. Restifo

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Figure 3

Ciprofloxacin treatment impairs the effectiveness of ACT therapy and reduces activation of the innate immune system in irradiated mice.

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Ciprofloxacin treatment impairs the effectiveness of ACT therapy and red...
(A) Ciprofloxacin reduced the detectable level of LPS in serum. Serum from nonirradiated and 5 Gy irradiated mice left untreated or treated with ciprofloxacin (Cipro) was collected and analyzed for the presence of microbial LPS using a limulus amebocyte lysate assay. Data (n = 3 per group) are representative of 2 independent experiments. (B) Ciprofloxacin treatment reduced the absolute number of host DCs. One day after TBI, splenocytes were isolated from nonirradiated and 5 Gy irradiated mice left untreated or treated with ciprofloxacin. Absolute numbers of CD11c+CD86high DCs were determined in the spleens of nonirradiated and irradiated mice. Data (n = 3 per group) are representative of 2 independent experiments. Horizontal bars indicate means. (C) Treatment of irradiated hosts with ciprofloxacin reduced effectiveness of ACT treatment. C57BL/6 mice bearing s.c. B16F10 tumors established for 10 days received 5 Gy TBI. One day later, mice received an ACT treatment consisting of adoptive transfer of 106 cultured pmel-1 T cells, rFPhgp100 vaccination, and rhIL-2 or were left untreated. Administration of ciprofloxacin as indicated began 2 days prior to ACT and continued for 2 weeks after treatment. Data (mean ± SEM; n = 4–5 per group) are representative of 2 independent experiments. †P = 0.05, ††P < 0.05 versus 5 Gy TBI without ciprofloxacin; ‡‡P < 0.001 versus 5 Gy TBI plus treatment without ciprofloxacin.