Skip to main content
Top
Published in: Seminars in Immunopathology 2/2009

01-07-2009 | Review

Colitis-associated cancer: the role of T cells in tumor development

Authors: Maximilian J. Waldner, Markus F. Neurath

Published in: Seminars in Immunopathology | Issue 2/2009

Login to get access

Abstract

Chronic inflammation severely increases the risk for cancer development as seen in patients with inflammatory bowel disease (IBD). Although the exact mechanisms of inflammation-associated tumor development remain to be shown, a role for the adaptive immune system has been implicated in colitis-associated cancer (CAC). In fact, CD4+ effector T cells, which promote chronic inflammation in IBD, create a tumor convenient environment, which can lead to cancer initiation, promotion, and progression. Thereby, the cytokines interleukin-6 and tumor necrosis factor-α constitute an important link between inflammation and tumor growth. Furthermore, cytotoxic CD8+ T cells, which usually are protective as part of the host antitumor immune response in sporadic cancer, can contribute to the aggravation of chronic inflammation and thereby support tumor development. In contrast, regulatory T cells, which have been shown to attenuate tumor immunosurveillance, act as potent suppressors of chronic inflammation and thus can have protective effects in CAC. This review discusses the role of the adaptive immune response and especially T cells in the pathogenesis CAC and possible implications for the therapeutic applications.
Literature
1.
go back to reference Gyde S, Prior P, Dew MJ, Saunders V, Waterhouse JA, Allan RN (1982) Mortality in ulcerative colitis. Gastroenterology 83:36–43PubMed Gyde S, Prior P, Dew MJ, Saunders V, Waterhouse JA, Allan RN (1982) Mortality in ulcerative colitis. Gastroenterology 83:36–43PubMed
8.
go back to reference Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA et al (1996) Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 157:1261–1270PubMed Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA et al (1996) Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 157:1261–1270PubMed
16.
go back to reference Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S et al (2008) Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 118:560–570. doi:10.1172/JCI32453 PubMed Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S et al (2008) Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 118:560–570. doi:10.​1172/​JCI32453 PubMed
17.
go back to reference Neurath MF, Pettersson S, Meyer Zum Büschenfelde KH, Strober W (1996) Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nat Med 2:998–1004. doi:10.1038/nm0996-998 CrossRefPubMed Neurath MF, Pettersson S, Meyer Zum Büschenfelde KH, Strober W (1996) Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nat Med 2:998–1004. doi:10.​1038/​nm0996-998 CrossRefPubMed
22.
go back to reference Yamamoto M, Yoshizaki K, Kishimoto T, Ito H (2000) IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol 164:4878–4882PubMed Yamamoto M, Yoshizaki K, Kishimoto T, Ito H (2000) IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol 164:4878–4882PubMed
23.
go back to reference Rose-John S, Scheller J, Elson G, Jones SA (2006) Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 80:227–236. doi:10.1189/jlb.1105674 CrossRefPubMed Rose-John S, Scheller J, Elson G, Jones SA (2006) Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 80:227–236. doi:10.​1189/​jlb.​1105674 CrossRefPubMed
26.
go back to reference Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20. doi:10.1042/BJ20030407 CrossRefPubMed Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20. doi:10.​1042/​BJ20030407 CrossRefPubMed
28.
go back to reference Galizia G, Orditura M, Romano C, Lieto E, Castellano P, Pelosio L et al (2002) Prognostic significance of circulating IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery. Clin Immunol 102:169–178. doi:10.1006/clim.2001.5163 CrossRefPubMed Galizia G, Orditura M, Romano C, Lieto E, Castellano P, Pelosio L et al (2002) Prognostic significance of circulating IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery. Clin Immunol 102:169–178. doi:10.​1006/​clim.​2001.​5163 CrossRefPubMed
30.
go back to reference Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T et al (2009) gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15:91–102. doi:10.1016/j.ccr.2009.01.002 CrossRefPubMed Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T et al (2009) gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15:91–102. doi:10.​1016/​j.​ccr.​2009.​01.​002 CrossRefPubMed
31.
33.
go back to reference Osawa E, Nakajima A, Fujisawa T, Kawamura YI, Toyama-Sorimachi N, Nakagama H et al (2006) Predominant T helper type 2-inflammatory responses promote murine colon cancers. Int J Cancer 118:2232–2236. doi:10.1002/ijc.21639 CrossRefPubMed Osawa E, Nakajima A, Fujisawa T, Kawamura YI, Toyama-Sorimachi N, Nakagama H et al (2006) Predominant T helper type 2-inflammatory responses promote murine colon cancers. Int J Cancer 118:2232–2236. doi:10.​1002/​ijc.​21639 CrossRefPubMed
34.
go back to reference Strasly M, Cavallo F, Geuna M, Mitola S, Colombo MP, Forni G et al (2001) IL-12 inhibition of endothelial cell functions and angiogenesis depends on lymphocyte-endothelial cell cross-talk. J Immunol 166:3890–3899PubMed Strasly M, Cavallo F, Geuna M, Mitola S, Colombo MP, Forni G et al (2001) IL-12 inhibition of endothelial cell functions and angiogenesis depends on lymphocyte-endothelial cell cross-talk. J Immunol 166:3890–3899PubMed
35.
go back to reference Verbik DJ, Stinson WW, Brunda MJ, Kessinger A, Joshi SS (1996) In vivo therapeutic effects of interleukin-12 against highly metastatic residual lymphoma. Clin Exp Metastasis 14:219–229PubMed Verbik DJ, Stinson WW, Brunda MJ, Kessinger A, Joshi SS (1996) In vivo therapeutic effects of interleukin-12 against highly metastatic residual lymphoma. Clin Exp Metastasis 14:219–229PubMed
37.
go back to reference Nastala CL, Edington HD, McKinney TG, Tahara H, Nalesnik MA, Brunda MJ et al (1994) Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J Immunol 153:1697–1706PubMed Nastala CL, Edington HD, McKinney TG, Tahara H, Nalesnik MA, Brunda MJ et al (1994) Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J Immunol 153:1697–1706PubMed
40.
go back to reference Shibata M, Nezu T, Kanou H, Abe H, Takekawa M, Fukuzawa M (2002) Decreased production of interleukin-12 and type 2 immune responses are marked in cachectic patients with colorectal and gastric cancer. J Clin Gastroenterol 34:416–420. doi:10.1097/00004836-200204000-00006 CrossRefPubMed Shibata M, Nezu T, Kanou H, Abe H, Takekawa M, Fukuzawa M (2002) Decreased production of interleukin-12 and type 2 immune responses are marked in cachectic patients with colorectal and gastric cancer. J Clin Gastroenterol 34:416–420. doi:10.​1097/​00004836-200204000-00006 CrossRefPubMed
41.
go back to reference Kettunen HL, Kettunen AS, Rautonen NE (2003) Intestinal immune responses in wild-type and Apcmin/+ mouse, a model for colon cancer. Cancer Res 63:5136–5142PubMed Kettunen HL, Kettunen AS, Rautonen NE (2003) Intestinal immune responses in wild-type and Apcmin/+ mouse, a model for colon cancer. Cancer Res 63:5136–5142PubMed
42.
go back to reference Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666. doi:10.1056/NEJMoa051424 CrossRefPubMed Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666. doi:10.​1056/​NEJMoa051424 CrossRefPubMed
43.
44.
go back to reference Weedon DD, Shorter RG, Ilstrup DM, Huizenga KA, Taylor WF (1973) Crohn's disease and cancer. N Engl J Med 289:1099–1103PubMed Weedon DD, Shorter RG, Ilstrup DM, Huizenga KA, Taylor WF (1973) Crohn's disease and cancer. N Engl J Med 289:1099–1103PubMed
48.
go back to reference Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F et al (1997) Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology 112:1169–1178. doi:10.1016/S0016-5085(97)70128-8 CrossRefPubMed Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F et al (1997) Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology 112:1169–1178. doi:10.​1016/​S0016-5085(97)70128-8 CrossRefPubMed
49.
go back to reference Stuber E, Strober W, Neurath M (1996) Blocking the CD40L–CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion. J Exp Med 183:693–698. doi:10.1084/jem.183.2.693 CrossRefPubMed Stuber E, Strober W, Neurath M (1996) Blocking the CD40L–CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion. J Exp Med 183:693–698. doi:10.​1084/​jem.​183.​2.​693 CrossRefPubMed
52.
55.
59.
go back to reference Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B et al (2006) IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116:1310–1316. doi:10.1172/JCI21404 CrossRefPubMed Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B et al (2006) IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116:1310–1316. doi:10.​1172/​JCI21404 CrossRefPubMed
60.
go back to reference Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C et al (2008) RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology . doi:10.1053/j.gastro.2008.10.018 PubMed Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C et al (2008) RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology . doi:10.​1053/​j.​gastro.​2008.​10.​018 PubMed
61.
go back to reference Seiderer J, Elben I, Diegelmann J, Glas J, Stallhofer J, Tillack C et al (2008) Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm Bowel Dis 14:437–445. doi:10.1002/ibd.20339 CrossRefPubMed Seiderer J, Elben I, Diegelmann J, Glas J, Stallhofer J, Tillack C et al (2008) Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm Bowel Dis 14:437–445. doi:10.​1002/​ibd.​20339 CrossRefPubMed
67.
go back to reference Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H et al (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494PubMed Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H et al (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494PubMed
68.
go back to reference Atreya I, Schimanski CC, Becker C, Wirtz S, Dornhoff H, Schnürer E et al (2007) The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer. Gut 56:1572–1578. doi:10.1136/gut.2006.117812 CrossRefPubMed Atreya I, Schimanski CC, Becker C, Wirtz S, Dornhoff H, Schnürer E et al (2007) The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer. Gut 56:1572–1578. doi:10.​1136/​gut.​2006.​117812 CrossRefPubMed
71.
go back to reference Michael-Robinson JM, Pandeya N, Walsh MD, Biemer-Huttmann AE, Eri RD, Buttenshaw RL et al (2006) Characterization of tumour-infiltrating lymphocytes and apoptosis in colitis-associated neoplasia: comparison with sporadic colorectal cancer. J Pathol 208:381–387. doi:10.1002/path.1895 CrossRefPubMed Michael-Robinson JM, Pandeya N, Walsh MD, Biemer-Huttmann AE, Eri RD, Buttenshaw RL et al (2006) Characterization of tumour-infiltrating lymphocytes and apoptosis in colitis-associated neoplasia: comparison with sporadic colorectal cancer. J Pathol 208:381–387. doi:10.​1002/​path.​1895 CrossRefPubMed
72.
go back to reference Müller S, Lory J, Corazza N, Griffiths GM, Z'graggen K, Mazzucchelli L et al (1998) Activated CD4+ and CD8+ cytotoxic cells are present in increased numbers in the intestinal mucosa from patients with active inflammatory bowel disease. Am J Pathol 152:261–268PubMed Müller S, Lory J, Corazza N, Griffiths GM, Z'graggen K, Mazzucchelli L et al (1998) Activated CD4+ and CD8+ cytotoxic cells are present in increased numbers in the intestinal mucosa from patients with active inflammatory bowel disease. Am J Pathol 152:261–268PubMed
73.
go back to reference Souza HS, Tortori CJ, Castelo-Branco MT, Carvalho AT, Margallo VS, Delgado CF et al (2005) Apoptosis in the intestinal mucosa of patients with inflammatory bowel disease: evidence of altered expression of FasL and perforin cytotoxic pathways. Int J Colorectal Dis 20:277–286. doi:10.1007/s00384-004-0639-8 CrossRefPubMed Souza HS, Tortori CJ, Castelo-Branco MT, Carvalho AT, Margallo VS, Delgado CF et al (2005) Apoptosis in the intestinal mucosa of patients with inflammatory bowel disease: evidence of altered expression of FasL and perforin cytotoxic pathways. Int J Colorectal Dis 20:277–286. doi:10.​1007/​s00384-004-0639-8 CrossRefPubMed
74.
go back to reference Okazaki K, Morita M, Nishimori I, Sano S, Toyonaga M, Nakazawa Y et al (1993) Major histocompatibility antigen-restricted cytotoxicity in inflammatory bowel disease. Gastroenterology 104:384–391PubMed Okazaki K, Morita M, Nishimori I, Sano S, Toyonaga M, Nakazawa Y et al (1993) Major histocompatibility antigen-restricted cytotoxicity in inflammatory bowel disease. Gastroenterology 104:384–391PubMed
75.
go back to reference Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L et al (2006) Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest 116:1713–1722. doi:10.1172/JCI25112 CrossRefPubMed Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L et al (2006) Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest 116:1713–1722. doi:10.​1172/​JCI25112 CrossRefPubMed
77.
78.
79.
go back to reference Read S, Malmström V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+) CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192:295–302. doi:10.1084/jem.192.2.295 CrossRefPubMed Read S, Malmström V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+) CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192:295–302. doi:10.​1084/​jem.​192.​2.​295 CrossRefPubMed
82.
go back to reference Berg DJ, Davidson N, Kühn R, Müller W, Menon S, Holland G et al (1996) Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest 98:1010–1020. doi:10.1172/JCI118861 CrossRefPubMed Berg DJ, Davidson N, Kühn R, Müller W, Menon S, Holland G et al (1996) Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest 98:1010–1020. doi:10.​1172/​JCI118861 CrossRefPubMed
83.
go back to reference Poutahidis T, Haigis KM, Rao VP, Nambiar PR, Taylor CL, Ge Z et al (2007) Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma. Carcinogenesis 28:2614–2623. doi:10.1093/carcin/bgm180 CrossRefPubMed Poutahidis T, Haigis KM, Rao VP, Nambiar PR, Taylor CL, Ge Z et al (2007) Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma. Carcinogenesis 28:2614–2623. doi:10.​1093/​carcin/​bgm180 CrossRefPubMed
85.
go back to reference Wolf D, Wolf AM, Rumpold H, Fiegl H, Zeimet AG, Muller-Holzner E et al (2005) The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 11:8326–8331. doi:10.1158/1078-0432.CCR-05-1244 CrossRefPubMed Wolf D, Wolf AM, Rumpold H, Fiegl H, Zeimet AG, Muller-Holzner E et al (2005) The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 11:8326–8331. doi:10.​1158/​1078-0432.​CCR-05-1244 CrossRefPubMed
86.
go back to reference Ishibashi Y, Tanaka S, Tajima K, Yoshida T, Kuwano H (2006) Expression of Foxp3 in non-small cell lung cancer patients is significantly higher in tumor tissues than in normal tissues, especially in tumors smaller than 30 mm. Oncol Rep 15:1315–1319PubMed Ishibashi Y, Tanaka S, Tajima K, Yoshida T, Kuwano H (2006) Expression of Foxp3 in non-small cell lung cancer patients is significantly higher in tumor tissues than in normal tissues, especially in tumors smaller than 30 mm. Oncol Rep 15:1315–1319PubMed
Metadata
Title
Colitis-associated cancer: the role of T cells in tumor development
Authors
Maximilian J. Waldner
Markus F. Neurath
Publication date
01-07-2009
Publisher
Springer-Verlag
Published in
Seminars in Immunopathology / Issue 2/2009
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-009-0161-8

Other articles of this Issue 2/2009

Seminars in Immunopathology 2/2009 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine