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Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling
Open accessAbstract
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.
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“A number of studies have shown that the gut microbiome may influence anti-tumor immune responses via innate and adaptive immunity (11, 12)”
From Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients (2018) · cites this paper as [11]
In the citing paper
“In mouse models, certain gut commensals mediate efficacy of anticancer therapies, including chemotherapy, radiotherapy, and immunotherapies such as adoptive T cell transfer, intratumoral CpG-oligonucleotides, and ICIs.”
From Melanoma and microbiota: Current understanding and future directions (2024) · cites this paper as [2]
In the citing paper
“total-body irradiation, which enhanced the efficacy of tumor-specific T cell transfer through translocation of a bacterial product, the toll-like receptor 4L (TLR4L) lipopolysaccharide, from the intestinal lumen to secondary lymphoid organs (10).”
From The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies (2018) · cites this paper as [10]
In the citing paper
“administration of antibiotics significantly abrogated anti-tumor activity in a murine model of adoptive cell therapy for melanoma”
From The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy (2018) · cites this paper as Paulos et al., 2007
In the citing paper
“For example, the widely studied bacterial lipopolysaccharide (LPS), a major component of the outer membrane in gram-negative bacteria, activates the host’s cell surface receptor toll-like receptor 4 (TLR4), belonging to the family of pattern recognition receptors (PRRs), thus activating immune T cell-mediated response against cancer cells [40].”
From Gut Microbiota and Cancer: From Pathogenesis to Therapy (2019) · cites this paper as [40]
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Metadata
- Authors
- Paulos, C. M., Wrzesinski, C., Kaiser, Hinrichs, C. S., Chieppa, M., Cassard, L., Palmer, D. C., Boni, A., Muranski, P., Yu, Z., Gattinoni, L., Antony, P. A., Rosenberg, S. A., & Restifo, N. P.
- Affiliations
- National Institutes of Health (US)
- National Cancer Institute (US)
- Johns Hopkins University (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2007-08-01
- Volume
- 117
- Issue
- 8
- Pages
- 2197-2204
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1924500
- OpenAlex
- W2153512326
- Cited by
- 586
- References
- 63
- Citations by year
- 2026: 20 · 2025: 43 · 2024: 40 · 2023: 42 · 2022: 42 · 2021: 51 · 2020: 49 · 2019: 36 · 2018: 26 · 2017: 32 · 2016: 23 · 2015: 29 · 2014: 27 · 2013: 20 · 2012: 23
- FWCI
- 8.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- AIRUS (submittedVersion)
- Funders
- National Institutes of Health (Z99 CA999999)
- National Cancer Institute (Z01BC010763)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- microbial translocation, total body irradiation, lymphocyte depletion, adoptive T cell therapy, CD8+ T cells, TLR4 signaling, lipopolysaccharide, commensal gut microbiota, dendritic cell activation, inflammatory cytokines, cancer immunotherapy, B16F10 melanoma, vitiligo, CD14
- MeSH terms
- Animals, Anti-Bacterial Agents, Autoimmune Diseases, Intestines, Lipopolysaccharides, Lymphocyte Depletion, Lymphocyte Activation, Neoplasm Transplantation, Neoplasms, Experimental, Polymyxin B, Vitiligo, Whole-Body Irradiation, Signal Transduction, Autoimmunity, Cytokines, CD8-Positive T-Lymphocytes, Lipopolysaccharide Receptors, Bacterial Translocation, Adoptive Transfer, Cell Line, Tumor, Toll-Like Receptor 4, Mice
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