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 6

Administration of ultrapure LPS after TBI significantly enhances antitumor immunity and autoimmunity.

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Administration of ultrapure LPS after TBI significantly enhances antitum...
(A) Ultrapure LPS augmented antitumor responses in irradiated mice. 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. The next day, mice received ultrapure LPS or were left untreated. Data (mean ± SEM; n = 5–10 per group) are representative of 10 independent experiments. (B) LPS enhanced autoimmune vitiligo in irradiated mice. One month after ACT treatment, irradiated mice treated with or without ultra-pure LPS were evaluated for the development of vitiligo. Mice were scored for the degree of hypopigmentation on a scale of 0–5. Data (n = 4–5 per group) are from 3 independent experiments. Horizontal bars indicate means. (C) Ultrapure LPS increased the absolute number of transferred pmel-1 T cells in the irradiated host. Absolute numbers of transferred pmel-1 T cells (CD8+Thy1.1+) in irradiated host. Data (mean ± SEM; n = 3–5 per group) are representative of 2 independent experiments. (D) Ultrapure LPS enhanced the function of adoptively transferred cells in irradiated mice. Five days after ACT treatment, pmel-1–Thy1.1+ splenocytes were cocultured with irradiated splenocytes pulsed with the indicated doses of hpg10025–33. Unpulsed splenocytes were used as controls. Data (mean ± SEM; n = 3 per group) are representative of 2 independent experiments. ††P < 0.05, ‡‡P < 0.001 versus irradiated treated mice.