Unifying roles for regulatory T cells and inflammation in cancer - PubMed (original) (raw)
Unifying roles for regulatory T cells and inflammation in cancer
Susan E Erdman et al. Int J Cancer. 2010.
Abstract
Activities of CD4(+) regulatory (T(REG)) cells restore immune homeostasis during chronic inflammatory disorders. Roles for T(REG) cells in inflammation-associated cancers, however, are paradoxical. It is widely believed that T(REG) function in cancer mainly to suppress protective anticancer responses. However, we demonstrate here that T(REG) cells also function to reduce cancer risk throughout the body by efficiently downregulating inflammation arising from the gastrointestinal (GI) tract. Building on a "hygiene hypothesis" model in which GI infections lead to changes in T(REG) that reduce immune-mediated diseases, here we show that gut bacteria-triggered T(REG) may function to inhibit cancer even in extraintestinal sites. Ability of bacteria-stimulated T(REG) to suppress cancer depends on interleukin (IL)-10, which serves to maintain immune homeostasis within bowel and support a protective antiinflammatory T(REG) phenotype. However, under proinflammatory conditions, T(REG) may fail to provide antiinflammatory protection and instead contribute to a T helper (Th)-17-driven procarcinogenic process; a cancer state that is reversible by downregulation of inflammation. Consequently, hygienic individuals with a weakened IL-10 and T(REG)-mediated inhibitory loop are highly susceptible to the carcinogenic consequences of elevated IL-6 and IL-17 and show more frequent inflammation-associated cancers. Taken together, these data unify seemingly divergent disease processes such as autoimmunity and cancer and help explain the paradox of T(REG) and inflammation in cancer. Enhancing protective T(REG) functions may promote healthful longevity and significantly reduce risk of cancer.
Figures
Figure 1
Interleukin-10-dependent functions of regulatory T cells restore immune homeostasis in 129 strain Rag2-deficient mice. (a) Gene expression of IL-6 and IL-17 were elevated (p < 0.05) within colonic tissues of infected recipients of _IL10_-deficient Treg cells. For comparison of mRNA levels, the target mRNA was normalized to that of the housekeeping gene GAPDH. Numbers on the _y_-axis represent mean fold change of target mRNA levels in reference to the control levels (B6 wt, defined as 0, standard deviation represented by solid bars). mos = age in months on necropsy. *p values were compared with the control. (b) Immunohistochemical staining illustrates overexpression of IL-17 in the mesenteric lymph nodes of mice lacking IL-10. The aberrant immunostaining pattern observed in IL-10−/− animals after infection with H. hepaticus can be appreciated by comparison with tissues of wt mice (top row). The carcinogenic effect was isolated to IL-10-deficient lymphocytes and was correlated with overexpression of IL-17. 3,3-Diaminobenzidine, hematoxylin counterstain. Bars: 25 μm. (c) Overview of interrelated pathways of inflammation involving Treg cells, IL-6 and IL-17 contributing to cancer development and growth. (d) Purified TREG cells of differing dosages or genotypes functioned differently, but these differences are not the result of differential expansion or recruitment of cells within lymph nodes. Each plot indicates % of MLN cells in the live cell gate that express CD4. The second number represents the % of CD4+ cells that expressed Foxp3.
Figure 2
Gut bacteria-triggered TREG cells protect against intestinal and mammary neoplasia and increase survival. (a) Levels of TNF-α and IL-17 were significantly (p < 0.01) elevated in female Min mice. Serum cytokine levels of 5 months old C57Bl/6 wt (blue bars) and APCMin/+ mice (green bars) were measured using the Bioplex assay system. Statistically significant higher levels of TNF-α, IL-9 and IL-17 were detected in APC Min/+ mice. *p < 0.05; **p < 0.01. (b) TREG cells from “hygienic” Treg cell donors failed to reduce gene expression of IL-6 and IL-17. Levels of IL-6 and IL-17 were elevated (p < 0.05) within ileal and mammary tissues of recipients of TEFF cells. (c) Adoptive transfer of purified TEFF cells cause highly infiltrative mammary adenosquamous carcinoma in female APC Min/+ mice. Foxp3+ cells (right panel arrow) locate within tumor-associated inflammatory cell foci at the margins of tumors. The right panel provides a higher magnification of the same field. 3,3-Diaminobenzidine, hematoxylin counterstain. Bars: left panel: 100 μm; right panel: 25 μm. (d) Survival curve illustrating increased lifespan in APC Min/+ mouse recipients of TREG cells from _H. hepaticus_-infected syngeneic wt donor mice. For the survival curve, mice were humanely euthanized using institutional criteria (i.e., poor body condition score, large tumor size) or when exhibiting other signs of distress.
Figure 3
Neutralization of TNF-α restores epithelial and immune homeostasis in FVB strain HER2/neu mice. To directly test requirements for inflammation in mammary cancer, we used anti-TNF-α treatment in HER2/neu mice. We selected 6-month-old HER2/neu mice with a small but established tumor burden. Anti-TNF-α was delivered by intraperitoneal injection ×3 weekly for 10 days and then underwent necropsy immediately afterward. Mammary tumor counts were based on grossly evident tumor nodules in mammary tissue on necropsy and then compared between groups by unpaired Student’s t test. Mammary tumor volumes (cm3) were estimated based on dimensions of solid tumor tissue (excluding fluid-filled cysts) on necropsy and then were compared between groups using Mann–Whitney U analyses. (a) Blockade of TNF-α led to decreased tumor burden with significantly (p < 0.05) reduced volume and a trend (p = 0.07) toward fewer tumors in 6-month-old female HER2/neu mice. (b) Foxp3+ cells in untreated or sham mice were located within lymph nodes and inflammatory foci adjacent to, but not inside, mammary tumors. Treatment with anti-TNF-α significantly increased frequency of Foxp3+ cells within tumors. Similarly, anti-TNF-α treatment reduced (p < 0.05) the numbers of IL-17+ cells in mammary tumors (shown in right panels). Cell counts were performed as described in Material and Methods section. 3,3-Diaminobenzidine, hematoxylin counterstain. Bars: 25 μm.
Figure 4
Summary of tumor outcomes in different mouse models of cancer. Mouse models that mimic cancer in humans were consistent with the “hygiene hypothesis” and connected seemingly divergent disease phenotypes including autoimmunity and cancer. Bacteria-triggered IL-10-dependent functions of TREG cells protect from inflammation-associated cancer.
Figure 5
Conceptual overview of immune factors contributing to cancer development and growth under hygienic host conditions. Under normal physiological conditions, TREG responses are beneficial to the host by reinforcing protective acute inflammation and then afterward regain protection from pathologic sequellae of chronic inflammation. During a proinflammatory microbial challenge, elevated levels of IL-6 upregulate a T helper type (Th)-17 host response that contributes to cancer growth and invasion. [Color figure can be viewed in the online issue, which is available at
.]
Comment in
- Infection, inflammation and cancer.
Grange JM, Krone B, Mastrangelo G. Grange JM, et al. Int J Cancer. 2011 May 1;128(9):2240-1. doi: 10.1002/ijc.25533. Int J Cancer. 2011. PMID: 20602341 No abstract available.
Similar articles
- Roles for inflammation and regulatory T cells in colon cancer.
Erdman SE, Poutahidis T. Erdman SE, et al. Toxicol Pathol. 2010 Jan;38(1):76-87. doi: 10.1177/0192623309354110. Epub 2009 Dec 17. Toxicol Pathol. 2010. PMID: 20019355 Free PMC article. Review. - CD4+ lymphocytes modulate prostate cancer progression in mice.
Poutahidis T, Rao VP, Olipitz W, Taylor CL, Jackson EA, Levkovich T, Lee CW, Fox JG, Ge Z, Erdman SE. Poutahidis T, et al. Int J Cancer. 2009 Aug 15;125(4):868-78. doi: 10.1002/ijc.24452. Int J Cancer. 2009. PMID: 19408303 Free PMC article. - Lineage targeted MHC-II transgenic mice demonstrate the role of dendritic cells in bacterial-driven colitis.
Maggio-Price L, Seamons A, Bielefeldt-Ohmann H, Zeng W, Brabb T, Ware C, Lei M, Hershberg RM. Maggio-Price L, et al. Inflamm Bowel Dis. 2013 Jan;19(1):174-84. doi: 10.1002/ibd.23000. Inflamm Bowel Dis. 2013. PMID: 22619032 Free PMC article. - Toll-like receptor 4-mediated regulation of spontaneous Helicobacter-dependent colitis in IL-10-deficient mice.
Matharu KS, Mizoguchi E, Cotoner CA, Nguyen DD, Mingle B, Iweala OI, McBee ME, Stefka AT, Prioult G, Haigis KM, Bhan AK, Snapper SB, Murakami H, Schauer DB, Reinecker HC, Mizoguchi A, Nagler CR. Matharu KS, et al. Gastroenterology. 2009 Oct;137(4):1380-90.e1-3. doi: 10.1053/j.gastro.2009.07.004. Epub 2009 Aug 3. Gastroenterology. 2009. PMID: 19596011 Free PMC article. - Cancer inflammation and regulatory T cells.
Erdman SE, Poutahidis T. Erdman SE, et al. Int J Cancer. 2010 Aug 15;127(4):768-79. doi: 10.1002/ijc.25430. Int J Cancer. 2010. PMID: 20518013 Free PMC article. Review.
Cited by
- The role of intestinal flora on tumor immunotherapy: recent progress and treatment implications.
Zhou Y, Liu X, Gao W, Luo X, Lv J, Wang Y, Liu D. Zhou Y, et al. Heliyon. 2023 Dec 20;10(1):e23919. doi: 10.1016/j.heliyon.2023.e23919. eCollection 2024 Jan 15. Heliyon. 2023. PMID: 38223735 Free PMC article. Review. - The role of the symbiotic microecosystem in cancer: gut microbiota, metabolome, and host immunome.
Xue X, Li R, Chen Z, Li G, Liu B, Guo S, Yue Q, Yang S, Xie L, Zhang Y, Zhao J, Tan R. Xue X, et al. Front Immunol. 2023 Aug 24;14:1235827. doi: 10.3389/fimmu.2023.1235827. eCollection 2023. Front Immunol. 2023. PMID: 37691931 Free PMC article. Review. - Influence of the Oral Health Assessment Tool Score on Survival of Patients With Esophageal Cancer.
Tamagawa H, Tamagawa A, Aoyama T, Hashimoto I, Maezawa Y, Hara K, Kato A, Kamiya N, Otani K, Numata M, Kazama K, Morita J, Tanabe M, Onuma S, Cho H, Sawazaki S, Ohshima T, Yukawa N, Mitsudo K, Saito A, Rino Y. Tamagawa H, et al. In Vivo. 2023 Sep-Oct;37(5):2253-2259. doi: 10.21873/invivo.13327. In Vivo. 2023. PMID: 37652503 Free PMC article. - Exploring the Involvement of Gut Microbiota in Cancer Therapy-Induced Cardiotoxicity.
Kunika, Frey N, Rangrez AY. Kunika, et al. Int J Mol Sci. 2023 Apr 14;24(8):7261. doi: 10.3390/ijms24087261. Int J Mol Sci. 2023. PMID: 37108423 Free PMC article. Review. - The impact of the microbiome in cancer: Targeting metabolism of cancer cells and host.
Huang JT, Mao YQ. Huang JT, et al. Front Oncol. 2022 Nov 16;12:1029033. doi: 10.3389/fonc.2022.1029033. eCollection 2022. Front Oncol. 2022. PMID: 36465375 Free PMC article. Review.
References
- Weiss ST. Eat dirt—the hygiene hypothesis and allergic diseases. N Engl J Med. 2002;347:930–1. - PubMed
- Fox JG, Beck P, Dangler CA, Whary MT, Wang TC, Shi HN, Nagler-Anderson C. Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy. Nat Med. 2000;6:536–42. - PubMed
- Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005;6:353–60. - PubMed
- Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9. - PubMed
- Colombo MP, Piconese S. Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat Rev Cancer. 2007;7:880–7. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- T32RR07036/RR/NCRR NIH HHS/United States
- R01 CA108854/CA/NCI NIH HHS/United States
- T32 RR007036/RR/NCRR NIH HHS/United States
- P01 CA026731/CA/NCI NIH HHS/United States
- R01CA108854/CA/NCI NIH HHS/United States
- P01CA26731/CA/NCI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases
Research Materials