Abstract
Cancer cells may escape from host immune responses through active suppression of the immune response, but the detailed mechanisms in colorectal cancer remain to be elucidated. In this study, 108 colorectal tumor samples and their peritumoral tissues were collected for immunohistochemistry of infiltrating lymphocytes. Th1 and Tregs cells were determined by the positive expression of T-bet and FOXP3 proteins, respectively. The Tr1 cells were identified by CD49b and LAG-3 protein expression. IL-17-positive cells were identified by IL-17 expression. Results showed that the percentage of T-bet-positive cells was significantly decreased, while the percentages of IL-17-, FOXP3-, CD49b-, and LAG-3-positive cells were significantly increased in tumor tissues compared to that in peritumoral tissues. The ratio of IL-17-, FOXP3-, CD49b-, and LAG3-positive cells to T-bet-positive cells was significantly higher in tumor tissues than in peritumoral tissues. The percentage of infiltrating IL-17-positive cells in tumor tissues was negatively associated with lymph metastasis, invasion, and TNM stage. The percentage of CD49b- and LAG-3-positive cells was positively associated with differentiation, lymph metastasis, invasion, TNM, and Duke stage of colorectal cancer. The percentage of positive Th17 and Tr1 cells is a marker for poor prognosis in patients with CRC. In conclusion, decreased composition of regulative Th1 cells and increased composition of FOXP+ Tregs-, CD49b+/LAG-3+ Tr1-, and IL-17-positive cells in tumor tissues may be associated with the progression of colorectal cancer. The high percentage of IL-17- and Tr1-positive cells in tumor tissues is a predictive marker for poor prognosis of colorectal cancer.
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Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.
Pitule P, Vycital O, Bruha J, Novak P, Hosek P, Treska V, Hlavata I, Soucek P, Kralickova M, Liska V. Differential expression and prognostic role of selected genes in colorectal cancer patients. Anticancer Res. 2013;33:4855–65.
De Sousa E, Melo F, Wang X, Jansen M, Fessler E, Trinh A, de Rooij LP, de Jong JH, de Boer OJ, van Leersum R, Bijlsma MF, Rodermond H, van der Heijden M, van Noesel CJ, Tuynman JB, Dekker E, Markowetz F, Medema JP, Vermeulen L. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. 2013;19:614–8.
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.
de la Cruz-Merino L, Henao Carrasco F, Vicente Baz D, Nogales Fernández E, Reina Zoilo JJ, Pulido EG, Codes Manuel de Villena M. Immune microenvironment in colorectal cancer: a new hallmark to change old paradigms. Clin Dev Immunol. 2011;2011:174149.
De La Cruz-Merino L, Grande-Pulido E, Albero-Tamarit A, De Villena MECM. Cancer and immune response: old and new evidence for future challenges. Oncologist. 2008;13:1246–54.
Luckheeram RV, Zhou R, Verma AD, Xia B. CD4+T cells: differentiation and functions. Clin Dev Immunol. 2012;2012:925135.
Raghavan S, Quiding-Järbrink M. Regulatory T cells in gastrointestinal tumors. Expert Rev Gastroenterol Hepatol. 2011;5:489–501.
Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100:655–69.
Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, Vernes JM, Jiang Z, Meng YG, Peale FV, Ouyang W, Ferrara N. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med. 2013;19:1114–23.
Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3 + regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother. 2011;60:909–18.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.
Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F, Di Serio C, Bacchetta R, Andreani M, Brockmann L, Gregori S, Flavell RA, Roncarolo MG. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013;19:739–46.
Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Investig. 2007;117:1137–46.
de la Cruz-Merino L, Henao Carrasco F, Vicente Baz D, Nogales Fernández E, Reina Zoilo JJ, Codes Manuel de Villena M, Pulido EG. Immune microenvironment in colorectal cancer: a new hallmark to change old paradigms. Clin Dev Immunol. 2011;2011:174149.
Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B. Tumor-infiltrating FOXP3 + T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27:186–92.
Correale P, Rotundo MS, Del Vecchio MT, Remondo C, Migali C, Ginanneschi C, Tsang KY, Licchetta A, Mannucci S, Loiacono L, Tassone P, Francini G, Tagliaferri P. Regulatory (FoxP3 +) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother. 2010;33:435–41.
Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, Oertli D, Kettelhack C, Terracciano L, Tornillo L. High frequency of tumor-infiltrating FOXP3 + regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer. 2010;126:2635–43.
Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, Giovannucci E, Dranoff G, Fuchs CS, Ogino S. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol. 2010;222:350–66.
Chaput N, Louafi S, Bardier A, Charlotte F, Vaillant JC, Menegaux F, Rosenzwajg M, Lemoine F, Klatzmann D, Taieb J. Identification of CD8 + CD25 + Foxp3 + suppressive T cells in colorectal cancer tissue. Gut. 2009;58:520–9.
Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH, Ziegler SF. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4 + CD25-T cells. J Clin Invest. 2003;112:1437–43.
Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004;21:589–601.
Magnani CF, Alberigo G, Bacchetta R, Serafini G, Andreani M, Roncarolo MG, Gregori S. Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur J Immunol. 2011;41:1652–62.
Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze MT. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003;101:2620–7.
Le Gouvello S, Bastuji-Garin S, Aloulou N, Mansour H, Chaumette MT, Berrehar F, Seikour A, Charachon A, Karoui M, Leroy K, Farcet JP, Sobhani I. High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas. Gut. 2008;57:772–9.
Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, Lin Z, Zhu B. IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma. Biochem Biophys Res Commun. 2011;407:348–54.
Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pagès F, Galon J. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011;71:1263–71.
Wang J, Xu K, Wu J, Luo C, Li Y, Wu X, Gao H, Feng G, Yuan BZ. The changes of Th17 cells and the related cytokines in the progression of human colorectal cancers. BMC Cancer. 2012;12:418.
Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, Bruneval P, Fridman WH, Becker C, Pagès F, Speicher MR, Trajanoski Z, Galon J. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39:782–95.
Halama N, Michel S, Kloor M, Zoernig I, Benner A, Spille A, Pommerencke T, von Knebel DM, Folprecht G, Luber B, Feyen N, Martens UM, Beckhove P, Gnjatic S, Schirmacher P, Herpel E, Weitz J, Grabe N, Jaeger D. Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res. 2011;71:5670–7.
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Chen, J., Chen, Z. The effect of immune microenvironment on the progression and prognosis of colorectal cancer. Med Oncol 31, 82 (2014). https://doi.org/10.1007/s12032-014-0082-9
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DOI: https://doi.org/10.1007/s12032-014-0082-9