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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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Singh, R. P., Bashir, H., & Kumar, R. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.06.008 · Cited by 34
Clinical effects and applications of the gut microbiome in hematologic malignancies
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“In line with this notion, exogenous LPS can substitute for the endogenous TBI-induced LPS for augmentation of the anti-tumor responses of CD8 T cells to active vaccination when they were adoptively transferred to immune cell (NK and CD4 T) cell-ablated recipient mice [96].”
Gut microbiota: A double-edged sword in immune checkpoint blockade immunotherapy against tumors
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Microbiome and host crosstalk: A new paradigm to cancer therapy
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Yao, Z., Jones, J. C., Kohrt, H. E. K., & Strober, S. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1101141 · Cited by 32
“This is due to WBCs in the transfusions that express minor histocompatibility Ags and immunize recipients to cross-reactive minor Ags in the donor graft.”
BackgroundInfluentialInflammatory Signals Regulate IL-15 in Response to Lymphodepletion
Anthony, S. M., Rivas, S., Colpitts, S. L., Howard, M. E., Stonier, S. W., & Schluns, K. S. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600219 · Cited by 32
“Whereas we observed sIL-15 complexes as early as 16 h post-TBI (data not shown), levels of serum LPS levels were not increased at this time, or at 24, 72, or 168 h postTBI (Fig.”
BackgroundInfluentialThe Gut Microbiota in Causation, Detection, and Treatment of Cancer
Murphy, C. L., O’Toole, P. W., & Shanahan, F. (2019) · The American Journal of Gastroenterology · doi:10.14309/ajg.0000000000000075 · Cited by 34
The role of the sex hormone-gut microbiome axis in tumor immunotherapy
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Influence of Microbiota on Tumor Immunotherapy
Yu, X., Li, W., Li, Z., Wu, Q., & Sun, S. (2024) · International Journal of Biological Sciences · doi:10.7150/ijbs.91771 · Cited by 33
“Initial evidence on the association between microbiota and ACT effectiveness was observed in a murine model with a deficiency in CD14 and TLR4 receptors [167].”
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Gut microbiota reshapes the TNBC immune microenvironment: Emerging immunotherapeutic strategies
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“It has also been shown that intestinal microorganisms can play an antitumor role by regulating innate immunity and acquired immunity [12], and it has also been found that probiotic CD8+TIL CD 4 + TI L”
The Microbiome and Its Implications in Cancer Immunotherapy
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“Additionally, recent evidence suggests that ligands for TLRs may circulate systemically due to radiation-induced damage, resulting in activation of host APC populations and increased triggering of T cells (76).”
BackgroundAttempting to Identify Bacterial Allies in Immunotherapy of NSCLC Patients
Grenda, A., Iwan, E., Krawczyk, P. A., Frąk, M., Chmielewska, I., Bomba, A., Giza, A., Rolska-Kopińska, A., Szczyrek, M., Kieszko, R., et al. (2022) · Cancers · doi:10.3390/cancers14246250 · Cited by 29
“Resident bacteria in the intestine can stimulate the immune system by modulating cytotoxic or helper T lymphocytes [15,16].”
BackgroundCombination Approaches to Immunotherapy: the Radiotherapy Example
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Strategies for Improving CAR T Cell Persistence in Solid Tumors
Wittling, M. C., Cole, A. C., Brammer, B., Diatikar, K. G., Schmitt, N. C., & Paulos, C. M. (2024) · Cancers · doi:10.3390/cancers16162858 · Cited by 31
Self-citationSystematic evaluation of immune regulation and modulation
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Arakawa, K., Ishigami, T., Nakai-Sugiyama, M., Chen, L., Doi, H., Kino, T., Minegishi, S., Saigoh-Teranaka, S., Nakashima-Sasaki, R., Hibi, K., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0218096 · Cited by 28
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Candidate immune biomarkers for radioimmunotherapy
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Unlocking the Complex Flavors of Dysgeusia after Hematopoietic Cell Transplantation
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Nelson, M. H., Bowers, J. S., Bailey, S. R., Diven, M. A., Fugle, C. W., Kaiser, A., Wrzesinski, C., Liu, B., Restifo, N. P., & Paulos, C. M. (2016) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-016-0110-8 · Cited by 27
“A non-myeloablative lymphodepleting preparative regimen with 5Gy TBI prior to an ACT regimen can induce destruction of B16F10 melanoma in mice by removing cytokine sinks, depleting suppressive Treg cells, transiently ablating myeloid derived suppressor cells (MDSCs) and activating the innate immune system [11].”
BackgroundResultInfluentialSelf-citationPolyphenol Mechanisms against Gastric Cancer and Their Interactions with Gut Microbiota: A Review
Li, M., Zheng, Y., Zhao, J., Liu, M., Shu, X., Li, Q., Wang, Y., & Zhou, Y. (2022) · Current Oncology · doi:10.3390/curroncol29080417 · Cited by 28
D'Angelo, C. R., Sudakaran, S., Asimakopoulos, F. A., Hematti, P., El‐Gamal, D., Safdar, N., & Callander, N. S. (2022) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2022.2131410 · Cited by 27
“immune system.[36] Separately, evidence from Sivan et.”
The impact of the microbiome in cancer: Targeting metabolism of cancer cells and host
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“Frontiers in Oncology 05 role of the gut microbiota in cancer therapy, showing that wholebody radiotherapy induces translocation of gram-negative microbiota and promotion of LPS release, thereby inducing TLR4-dependent activation of antigen-presenting cells and enhancing the efficacy of adoptive T-cell therapy (52).”
BackgroundA critical role of toll-like receptor 2 (TLR2) and its’ in vivo ligands in radio-resistance
Gao, F., Zhang, C., Zhou, C., Sun, W., Liu, X., Zhang, P., Han, J., Xian, L., Bai, D., Liu, H., et al. (2015) · Scientific Reports · doi:10.1038/srep13004 · Cited by 26
Challenges in Combining Immunotherapy with Radiotherapy in Recurrent/Metastatic Head and Neck Cancer
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“revealed that total body irradiation leads to gut bacteria translocation into mesenteric lymph nodes thus increasing antitumor CD8T cell adoptive transfer efficacy in a melanoma model.(4) Recently, this was confirmed in the cervix and lung tumor mice models by showing that ACT efficacy depends on native gut bacteria c…”
Background
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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