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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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Enhancing Immune Reconstitution: From Bench to Bedside
van den Brink, M. R. M., Leen, A. M., Baird, K., Merchant, M. S., Mackall, C. L., & Bollard, C. M. (2012) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2012.09.016 · Cited by 14
Saout, C. L., Villard, M., Cabasse, C., Jacquet, C., Taylor, N. N., & Hernández, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012659 · Cited by 14
“. Second, total body irradiation as well as the absence of Tregs may result in the generalized activation of APCs”
The Sunrise of Tertiary Lymphoid Structures in Cancer
Rochefort, J., Marodon, G., Teillaud, J., & Dieu‐Nosjean, M. (2025) · Immunological Reviews · doi:10.1111/imr.70046 · Cited by 13
“Commensal microbes can also activate CD8 + T cell-dependent antitumor responses [85], and enhance antitumor immunity by activating DCs via Toll-like receptor 4 (TLR4) signaling, particularly in murine melanoma models treated with radiotherapy, suggesting a DC-mediated TLS neogenesis pathway [91].”
The Interaction between Gut Microbiota and Host Amino Acids Metabolism in Multiple Myeloma
Yang, Q. Z., Wei, Y., Zhu, Y., Guo, J., Zhang, J., He, Y., Li, X., Liu, J., & Zhou, W. (2023) · Cancers · doi:10.3390/cancers15071942 · Cited by 13
“However, after the first demonstration that administration of antibiotics abrogated anti-tumor activity in a murine model of melanoma [92], the TEAMM results showed similar results, which demonstrated the higher mortality of MM patients with 12-week treatment of prophylactic levofloxacin [93].”
ResultThe Past, Present, and Future of Adoptive T Cell Therapy
Choi, D., Kim, T., & Sung, Y. C. (2012) · Immune Network · doi:10.4110/in.2012.12.4.139 · Cited by 13
“Moreover, administration of TLR agonists further enhance the efficacy of infused T cells, followed by a long-term cure of large tumors (71).”
BackgroundTherapeutic effects of iNOS inhibition against vitiligo in an animal model
Mansourpour, H., Ziari, K., Motamedi, S., & Poor, A. H. (2019) · European Journal of Translational Myology · doi:10.4081/ejtm.2019.8383 · Cited by 13
Innamarato, P., & Pilon‐Thomas, S. (2020) · Cellular Immunology · doi:10.1016/j.cellimm.2020.104277 · Cited by 12
“myeloablation) with ACT in combination HSCT could enhance tumor regression [12, 20, 21].”
BackgroundAdoptive Immunotherapy of Advanced Melanoma
Shapira‐Frommer, R., & Schachter, J. (2012) · Current Treatment Options in Oncology · doi:10.1007/s11864-012-0203-7 · Cited by 13
Angiogenic Cytokines Are Antibody Targets During Graft-versus-Leukemia Reactions
Piesche, M., Ho, V. T., Kim, H. T., Nakazaki, Y., Nehil, M., Yaghi, N. K., Kolodin, D., Weiser, J., Altevogt, P., Kiefel, H., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1956 · Cited by 13
Ward-Kavanagh, L. K., Zhu, J., Cooper, T. K., & Schell, T. D. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-13-0164 · Cited by 13
Cell-Permeable Peptide Blocks TLR4 Signaling and Improves Islet Allograft Survival
Dong, H., Zhang, Y., Song, L., Kim, D., Wu, H., Yang, L., Li, S., Morgan, K. A., Adams, D. B., & Wang, H. (2016) · Cell Transplantation · doi:10.3727/096368916x690449 · Cited by 13
Zheng, S., Li, K.-Z., Feng, G., Wang, Y.-T., Jia-ning, W. A. N. G., Li, S., & Sun, Y.-D. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02513-5 · Cited by 16
“In melanoma models undergoing radiotherapy, they activate DCs in a TLR4-dependent fashion, which in turn boosts T cell–driven antitumor responses [24].”
InfluentialColorectal cancer and microbiota: systematic review
Imanbayev, N. M., Iztleuov, Y. M., Bekmukhambetov, Y., Abdelazim, I. A., Donayeva, A., Amanzholkyzy, A., Zhumasheva, A., Imanbayeva, A., & Aslan, Y. (2024) · Gastroenterology Review · doi:10.5114/pg.2024.136228 · Cited by 13
“Paulos et al. [56] reported the microbiota’s role in immune response modulation.”
Li, P., Zhang, H., & Dai, M. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217274 · Cited by 14
Tüting, T. (2013) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12111 · Cited by 12
“Interestingly, the potent augmentation of ACT following total body irradiation also depended on TLR triggering (Paulos et al., 2007).”
BackgroundProfir, M., Roşu, O., Creţoiu, S. M., & Gașpar, B. S. (2024) · Microorganisms · doi:10.3390/microorganisms12050955 · Cited by 12
Antigenic Peptide Vaccination: Provoking Immune Response and Clinical Benefit for Cancer
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“This approach was augmented by total body irradiation for the further depletion of regulatory T cells and stimulation of innate immunity via Toll-like receptor (TLR) 4 [27, 28].”
Harnessing innate and adaptive immunity for adoptive cell therapy of renal cell carcinoma
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“In addition to the priming of naïve T cells, adjuvant utilization of DC vaccines in settings of adoptive transfer of NK, NKT, and γδ T cells, may prolong effector cell function and longevity [158, 159].”
BackgroundIneffective Vaccination against Solid Tumors Can Be Enhanced by Hematopoietic Cell Transplantation
Filatenkov, A., Müller, A. M. S., Tseng, W. W., Dejbakhsh‐Jones, S., Winer, D. A., Luong, R. H., Shizuru, J. A., Engleman, E. G., & Strober, S. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900159 · Cited by 12
“Previous studies indicate that the HSCs injected into irradiated mice not only prevented marrow aplasia, but also facilitated the expansion of CD8 T cells directed to melanoma tumor Ags by enhancing IL-7 and IL-15 production (22).”
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Lifestyle and Breast Cancer: Prevention and Treatment Support
Ratajczak, A. E., Jezierska, K., Szymczak‐Tomczak, A., Zawada, A. E., Rychter, A. M., Skoracka, K., Dobrowolska, A., & Krela‐Kaźmierczak, I. (2025) · Cancers · doi:10.3390/cancers17172830 · Cited by 12
“Through the interaction with bacterial lipopolysaccharide (LPS) on the outer membrane of Gram-negative bacteria, it activates Toll-like receptor 4 (TLR4) on the host cell surface, inducing an immune response of T cells against cancer cells [131].”
Nandi, D., & Sharma, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1477980 · Cited by 11
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Lerret, N. M., & Marzo, A. L. (2013) · OncoImmunology · doi:10.4161/onci.22731 · Cited by 11
The emerging roles of the gut microbiome in allogeneic hematopoietic stem cell transplantation
Khuat, L. T., Dave, M., & Murphy, W. J. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1966262 · Cited by 11
“dendritic cells) and cytokine storm triggering, therefore reducing gut permeability and tissue damage due to radiation sensitivity.(29,104) These evidences provide different perspectives of how one might consider choosing the “right type” of antibiotics to preserve the beneficial bacteria taxa without compromising tre…”
BackgroundWilson, K. A., Goding, S. R., Neely, H. R., Harris, K. M., & Antony, P. A. (2015) · OncoImmunology · doi:10.1080/2162402x.2015.1019196 · Cited by 12
“Lymphodepletion enhances ACT in multiple ways, including (1) the elimination of regulatory T cells (Tregs)(12), (2) the elimination of cells that use the same resources as the adoptively transferred T cells, termed cytokine sinks,(19) and (3) enhancing the availability and activation of APCs, presumably by allowing mo…”
BackgroundSelf-citationMiyahira, A. K., Roychowdhury, S., Goswami, S., Ippolito, J. E., Priceman, S. J., Pritchard, C. C., Sfanos, K. S., Subudhi, S. K., Simons, J. W., Pienta, K. J., et al. (2016) · The Prostate · doi:10.1002/pros.23260 · Cited by 11
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“However, when the Pmel-1 mice are exposed to total body irradiation, bacterial translocation from the damaged intestinal tract activates gp100-specific T cells and triggers an antimela-noma immune response (63).”
BackgroundIntravenous ascorbic acid as an adjuvant to interleukin-2 immunotherapy
Wagner, S. C., Markosian, B., Ajili, N., Dolan, B. R., Kim, A., Alexandrescu, D. T., Dasanu, C. A., Minev, B., Koropatnick, J. D., Marincola, F. M., et al. (2014) · Journal of Translational Medicine · doi:10.1186/1479-5876-12-127 · Cited by 10
“Given the potent effects seen clinically with homeostatically-induced lymphocyte activation [60], and the recent findings that T cell homeostatic proliferation appears to be associated with gut flora translocation [61], it may be possible that tumor suppressive activity of IL-2 may be highly dependent on the gut flora…”
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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