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 4

TLR4 signaling triggered by TBI improves the effectiveness of ACT therapy.

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TLR4 signaling triggered by TBI improves the effectiveness of ACT therap...
(A) Administration of PMB decreased the tumor treatment effectiveness of TBI. 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. For the duration of the experiment, mice were treated or not with PMB in their water. Data (mean ± SEM; n = 5 per group) are representative of 2 independent experiments. (B and C) The effectiveness of treatment was decreased in irradiated mice genetically deficient in CD14 (B) and TLR4 (C). WT, CD14–/–, and TLR4–/– tumor-bearing mice were irradiated and then received the ACT treatment described above or were left untreated. Data (mean ± SEM; n = 5 per group) are representative of 2 independent experiments. (D) Serum from irradiated mice improved treatment when transferred to nonirradiated antibody-lymphodepleted mice. Tumor-bearing mice received 5 Gy TBI or were left unirradiated. Alternatively, mice were depleted of lymphocytes with CD4 and NK antibodies and received 5 × 105 cultured pmel-1 T cells, rFPhgp100 vaccination, and IL-2 1 day later. Mice received serum with translocated LPS or serum removed of LPS with Detoxi-gel beads 1 day after ACT. Data (mean ± SEM; n = 4–5 per group) are representative of 2 independent experiments. ††P < 0.05, ‡P < 0.01 versus irradiated treated WT mice (A–C) or recipients of serum with LPS (D).