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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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“…as 2007, in a study of mouse melanoma models, translocated microbiota in mesenteric lymph nodes was found to enhance the function of adoptively transferred CD8 Akkermansia muciniphila T cells through TLR4 signaling, suggesting thatthemicrobiotacanstimulatethebody ’ santi-tumorimmuneresponse 33 .”
Human Tumor Xenografts: The Good, the Bad, and the Ugly
Morgan, R. A. (2012) · Molecular Therapy · doi:10.1038/mt.2012.73 · Cited by 69
Harnessing the Microbiome to Enhance Cancer Immunotherapy
Nelson, M. H., Diven, M. A., Huff, L. W., & Paulos, C. M. (2015) · Journal of Immunology Research · doi:10.1155/2015/368736 · Cited by 70
“Bacterial translocation activated the innate immune system, as indicated by the transient activation of host APCs that secreted heighten levels of proinflammatory cytokines in irradiated mice [6, 115–117].”
BackgroundInfluentialSelf-citationRadiation therapy and immunotherapy: Implications for a combined cancer treatment
Lévy, A., Chargari, C., Cheminant, M., Simon‐Tillaux, N., Bourgier, C., & Deutsch, É. (2012) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2012.09.001 · Cited by 72
Strategies to Improve the Efficacy of Dendritic Cell-Based Immunotherapy for Melanoma
Hargadon, K. M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01594 · Cited by 69
“Associated immunity to Melanoma The first study to report microbial influences on the outcome of immune therapy for cancer demonstrated that the therapeutic benefit of total body irradiation prior to adoptive T cell transfer arises in part from activation of the innate immune system following radiation-induced damage…”
BackgroundVivarelli, S., Costa, C., Teodoro, M., Giambò, F., Tsatsakis, A. M., & Fenga, C. (2022) · Archives of Toxicology · doi:10.1007/s00204-022-03391-2 · Cited by 69
Traditional Chinese Medicine and Gut Microbiome: Their Respective and Concert Effects on Healthcare
Zhang, R., Gao, X., Bai, H., & Ning, K. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00538 · Cited by 68
“The proliferation and antitumor cytotoxic activity of transferred T cells in the tumor were increased by the total-body irradiationinduced translocation of intestinal flora into the mesenteric lymph nodes (Paulos et al., 2007).”
BackgroundLi, S., Simoni, Y., Becht, É., Loh, C. Y., Li, N., Lachance, D. M., Koo, S., Lim, T. P., Tan, E., Mathew, R., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100039 · Cited by 70
“The first studies suggesting an immunotherapeutic effect of the microbiome showed improved effects of tumor-specific T cells by transferring bacterial products from the intestinal lumen to secondary lymphoid organs.(2) Ever since, the composition of the gut microbiota has been reported to influence anti-cancer therape…”
BackgroundT-Cell Immunotherapy: Looking Forward
Corrigan‐Curay, J., Kiem, H., Baltimore, D., O’Reilly, M., Brentjens, R. J., Cooper, L. J. N., Forman, S. J., Gottschalk, S. M., Greenberg, P. D., Junghans, R. P., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.148 · Cited by 65
Self-citationPancreatic Cancer, Gut Microbiota, and Therapeutic Efficacy
Zhang, X., Liu, Q., Liao, Q., & Zhao, Y. (2020) · Journal of Cancer · doi:10.7150/jca.37445 · Cited by 68
“Translocated bacteria enhanced the bioactivity of adoptively transferred CD8+ T cells and innate immunity [52].”
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Tumor-Associated Microbiome: Where Do We Stand?
Oliva, M., Mulet-Margalef, N., Ochoa-de-Olza, M., Napoli, S., Mas-Lloret, J., Laquente, B., Alemany, L., Duell, E. J., Nuciforo, P. G., & Moreno, V. R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031446 · Cited by 63
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“TBI induced a significant increase in the numbers of DCs, with comparable levels to those induced by CTX treatment.”
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Šahmatova, L., Tankov, S., Prans, E., Aab, A., Hermann, H., Reemann, P., Pihlap, M., Karelson, M., Abram, K., Kisand, K. E., et al. (2014) · Acta Dermato Venereologica · doi:10.2340/00015555-2394 · Cited by 63
NLRP3 inflammasomes that induce antitumor immunity
Zhivaki, D., & Kagan, J. C. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.05.001 · Cited by 61
Dutta, D., & Lim, S. H. (2020) · Biomarker Research · doi:10.1186/s40364-020-00211-6 · Cited by 61
Melatonin and Cancer: A Polyhedral Network Where the Source Matters
Bonmatí‐Carrión, M., & Tomás‐Loba, A. (2021) · Antioxidants · doi:10.3390/antiox10020210 · Cited by 59
Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts
Cui, Y., Zhang, H., Meadors, J. L., Poon, R., Guimond, M., & Mackall, C. L. (2009) · Blood · doi:10.1182/blood-2009-03-212134 · Cited by 60
Roles of microbiota in response to cancer immunotherapy
Inamura, K. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.12.026 · Cited by 62
Toll Like Receptors as Sensors of the Tumor Microbial Dysbiosis: Implications in Cancer Progression
Noci, V. L., Bernardo, G., Bianchi, F., Tagliabue, E., Sommariva, M., & Sfondrini, L. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.732192 · Cited by 60
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Postbiotic-Enabled Targeting of the Host-Microbiota-Pathogen Interface: Hints of Antibiotic Decline?
Puccetti, M., Xiroudaki, S., Ricci, M., & Giovagnoli, S. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12070624 · Cited by 59
“Postbiotics have also shown antiproliferative activity against colon cancer cells, likely by controlling immune responses and through the activation of pro-apoptotic cell death pathways [235,236].”
BackgroundGut microbiome homeostasis and the future of probiotics in cancer immunotherapy
Singh, A., Alexander, S., & Martin, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1114499 · Cited by 68
“In a distinct study, researchers found that the effectiveness of adoptive cell therapy after radiation is affected by a temporary infection of the gut microbiome and the activation of dendritic cells in the mesenteric lymph node (46).”
BackgroundGut microbiota: impacts on gastrointestinal cancer immunotherapy
Lau, H. C.-H., Sung, J. J. �., & Yu, J. Q. (2021) · Gut Microbes · doi:10.1080/19490976.2020.1869504 · Cited by 58
“The first evidence showing the correlation of gut microbiota with ACT efficacy was reported in 2007 when ACT plus total body irradiation (TBI; a form of lymphodepletion) were applied to a mouse model with a deficiency in a cluster of differentiation (Cd)-14 and Tlr-4.(22) Depleting microbiota by antibiotics or suppres…”
BackgroundThe Human Microbiota and Prostate Cancer: Friend or Foe?
Massari, F., Mollica, V., Nunno, V. D., Gatto, L., Santoni, M., Scarpelli, M., Cimadamore, A., Antonio Lopez-beltran, B., Liang Cheng, C., Battelli, N., et al. (2019) · Cancers · doi:10.3390/cancers11040459 · Cited by 58
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A critical role of toll-like receptor 4 (TLR4) and its’ in vivo ligands in basal radio-resistance
Liu, C., Zhang, C., Mitchel, R. E. J., Cui, J., Js, L., Yang, Y., Liu, X., & Cai, J. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.161 · Cited by 56
“Complete depletion of commensal microflora was verified by bacterial analysis of colonic feces using generally accepted methods, as described previously.(28)”
MethodInfluentialElia, A. R., Grioni, M., Basso, V., Curnis, F., Freschi, M., Corti, A., Mondino, A., & Bellone, M. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2210 · Cited by 58
“Nonmyeloablative, total body irradiation (TBI) was given to favor antigen-presenting cell activation (36) and to reduce competition for survival or proliferation signals (37).”
BackgroundCao, C., Yue, S., Lü, A., & Liang, C. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107321 · Cited by 64
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“The use of TLR agonists may even replace total body irradiation because it has recently been reported that this treatment modality depends on TLR triggering (50).”
BackgroundToll-like receptors in the pathogenesis of chemotherapy-induced gastrointestinal toxicity
Cario, E. (2016) · Current Opinion in Supportive and Palliative Care · doi:10.1097/spc.0000000000000202 · Cited by 55
“Chemotherapy-induced barrier dysfunction allows microbes to gain entry into deeper host tissues and circulating TLR ligands may provide essential adjuvant antitumor effects [69].”
BackgroundMolecular mimicry between tumor associated antigens and microbiota-derived epitopes
Ragone, C., Manolio, C., Mauriello, A., Cavalluzzo, B., Buonaguro, L., Tornesello, M. L., Tagliamonte, M., & Buonaguro, L. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03512-6 · Cited by 55
“Indeed, while components such as LPS or MPL activate T cell-mediated anti-cancer responses [21], the bacterial virulence factor Fap2 can inhibit Natural Killers [22].”
Background(2022) · doi:10.1016/j.hsr.2021.100010 · Cited by 69
Gut microbiome and CAR-T therapy
Abid, M. B., Shah, N. N., Maatman, T. C., & Hari, P. (2019) · Experimental Hematology and Oncology · doi:10.1186/s40164-019-0155-8 · Cited by 57
“[22] showed that the immune-enhancing effects of irradiation were dampened in mice receiving antibiotics in a melanoma mice model.”
BackgroundPeric, Z., Botti, S., Stringer, J., Krawczyk, J., van der Werf, S., van Biezen, A., Aljurf, M., Murray, J., Liptrott, S., Greenfield, D. M., et al. (2018) · Bone Marrow Transplantation · doi:10.1038/s41409-018-0137-1 · Cited by 54
Potential links between the microbiota and T cell immunity determine the tumor cell fate
Mohseni, A. H., Taghinezhad‐S, S., Casolaro, V., Lv, Z., & Li, D. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05560-2 · Cited by 54
“In 2007, for the first time, the beneficial role of the gut microbiota was demonstrated in protocols of adoptive T cell transfer, where commensal strains were shown to stimulate the activation of antigen-presenting cells (APCs) in a lipopolysaccharide (LPS)–Tolllike receptor 4 (TLR4) signaling-dependent manner [15].”
BackgroundAdjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy
Verdeil, G., Marquardt, K., Surh, C. D., & Sherman, L. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805054105 · Cited by 52
“We hypothesize that this combination of adjuvants may safely mimic the benefits to adoptive immunotherapy that are achieved by whole-body irradiation, whereby endogenous cytokines, removal of Tregs, and the release of TLR ligands from the gut play an important role in augmenting the activity of transferred CD8 T cells…”
BackgroundNovel immunotherapies for hematologic malignancies
Nelson, M. H., & Paulos, C. M. (2014) · Immunological Reviews · doi:10.1111/imr.12245 · Cited by 52
Self-citation
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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