Distinctive profiles of tumor-infiltrating immune cells and association with intensity of infiltration in colorectal cancer

Wu,Yugang; Yuan,Lei; Lu,Qicheng; Xu,Haiyan; He,Xiaozhou

doi:10.3892/ol.2018.7771

Distinctive profiles of tumor-infiltrating immune cells and association with intensity of infiltration in colorectal cancer

Authors:
- Yugang Wu
- Lei Yuan
- Qicheng Lu
- Haiyan Xu
- Xiaozhou He
View Affiliations

Affiliations: Department of Surgery, The Third Affiliated Hospital of Soochow University/The First People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China
Published online on: January 10, 2018 https://doi.org/10.3892/ol.2018.7771
Pages: 3876-3882

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Tumor-infiltrating immune cells are heterogeneous and consist of characteristic compartments, including T helper (Th)1 and regulatory T (Treg) cells that exhibit distinctive biological functions. The present study investigated the profile of infiltrating immune cells from surgically removed tumor tissues from patients with colorectal cancer. The characteristic transcription factors of Th1 and Th2 cells, Treg cells, Th17 cells and T follicular helper (Tfh) cells were analyzed. The results demonstrated that a marked increased number of Treg cells presented in tumor infiltrates when compared with non‑tumor adjacent tissues. An increased number of Th1 and Tfh cells existed in tumor infiltrates compared with non‑tumorous adjacent tissues, while the infiltration of Th17 and Th2 cells was similar between tumor and non‑tumor adjacent tissues. Furthermore, there were an increased number of Treg cells in tumors with low infiltration compared with those with high infiltration. The expression of CXC motif chemokine (CXC) receptor 3, CXC ligand (CXCL)L9 and CXCL10 was significantly increased on infiltrating T cells in tumors with high infiltration as compared with those with low infiltration. Macrophages exhibited a dominant M2 phenotype in tumor infiltrates of colorectal cancer, whereas a balanced M1 and M2 phenotype presented in macrophages from the peripheral blood. In vitro stimulation of macrophages isolated from tumor tissue of colorectal cancer with granulocyte macrophage colony‑stimulating factor and lipopolysaccharide did not drive to an inflammatory phenotype. The results provide insights into the pattern of immune cell infiltration in Chinese patients with colorectal cancer. It may be beneficial that patients with colorectal cancer are screened for the defined profile along with the expression of CXCL9 and CXCL10 in order to achieve better efficacy in clinical applications of immune‑based therapy, including anti-programmed cell death protein 1 therapy.

View Figures

View References

1	Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, Ohuchi A, Ohuchi K, Shiiba K, Kurokawa Y and Satomi S: Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: Possible association with suppression of micrometastasis. Br J Cancer. 91:1711–1717. 2004. View Article : Google Scholar : PubMed/NCBI
2	Diederichsen AC, Hjelmborg Jv, Christensen PB, Zeuthen J and Fenger C: Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol Immunother. 52:423–428. 2003. View Article : Google Scholar : PubMed/NCBI
3	Funada Y, Noguchi T, Kikuchi R, Takeno S, Uchida Y and Gabbert HE: Prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in colorectal cancer. Oncol Rep. 10:309–313. 2003.PubMed/NCBI
4	Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H and Ohtani H: CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 58:3491–3494. 1998.PubMed/NCBI
5	Oberg A, Samii S, Stenling R and Lindmark G: Different occurrence of CD8+, CD45R0+, and CD68+ immune cells in regional lymph node metastases from colorectal cancer as potential prognostic predictors. Int J Colorectal Dis. 17:25–29. 2002. View Article : Google Scholar : PubMed/NCBI
6	Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E and Kosma VM: Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol. 182:318–324. 1997. View Article : Google Scholar : PubMed/NCBI
7	Nagorsen D, Keilholz U, Rivoltini L, Schmittel A, Letsch A, Asemissen AM, Berger G, Buhr HJ, Thiel E and Scheibenbogen C: Natural T-cell response against MHC class I epitopes of epithelial cell adhesion molecule, her-2/neu, and carcinoembryonic antigen in patients with colorectal cancer. Cancer Res. 60:4850–4854. 2000.PubMed/NCBI
8	Nagorsen D, Scheibenbogen C, Marincola FM, Letsch A and Keilholz U: Natural T cell immunity against cancer. Clin Cancer Res. 9:4296–4303. 2003.PubMed/NCBI
9	Nagorsen D, Scheibenbogen C, Letsch A, Germer CT, Buhr HJ, Hegewisch-Becker S, Rivoltini L, Thiel E and Keilholz U: T cell responses against tumor associated antigens and prognosis in colorectal cancer patients. J Transl Med. 3:32005. View Article : Google Scholar : PubMed/NCBI
10	Blankenstein T: The role of tumor stroma in the interaction between tumor and immune system. Curr Opin Immunol. 17:180–186. 2005. View Article : Google Scholar : PubMed/NCBI
11	Kinnula VL, Torkkeli T, Kristo P, Sormunen R, Soini Y, Pääkkö P, Ollikainen T, Kahlos K, Hirvonen A and Knuutila S: Ultrastructural and chromosomal studies on manganese superoxide dismutase in malignant mesothelioma. Am J Respir Cell Mol Biol. 31:147–153. 2004. View Article : Google Scholar : PubMed/NCBI
12	Kojima M, Morisaki T, Tsukahara Y, Uchiyama A, Matsunari Y, Mibu R and Tanaka M: Nitric oxide synthase expression and nitric oxide production in human colon carcinoma tissue. J Surg Oncol. 70:222–229. 1999. View Article : Google Scholar : PubMed/NCBI
13	Nakamura Y, Yasuoka H, Tsujimoto M, Yoshidome K, Nakahara M, Nakao K, Nakamura M and Kakudo K: Nitric oxide in breast cancer: Induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin Cancer Res. 12:1201–1207. 2006. View Article : Google Scholar : PubMed/NCBI
14	Ahmed B and Van Den Oord JJ: Expression of the inducible isoform of nitric oxide synthase in pigment cell lesions of the skin. Br J Dermatol. 142:432–440. 2000. View Article : Google Scholar : PubMed/NCBI
15	Masri FA, Comhair SA, Koeck T, Xu W, Janocha A, Ghosh S, Dweik RA, Golish J, Kinter M, Stuehr DJ, et al: Abnormalities in nitric oxide and its derivatives in lung cancer. Am J Respir Crit Care Med. 172:597–605. 2005. View Article : Google Scholar : PubMed/NCBI
16	Vakkala M, Kahlos K, Lakari E, Pääkkö P, Kinnula V and Soini Y: Inducible nitric oxide synthase expression, apoptosis, and angiogenesis in in situ and invasive breast carcinomas. Clin Cancer Res. 6:2408–2416. 2000.PubMed/NCBI
17	Kono K, Salazar-Onfray F, Petersson M, Hansson J, Masucci G, Wasserman K, Nakazawa T, Anderson P and Kiessling R: Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity. Eur J Immunol. 26:1308–1313. 1996. View Article : Google Scholar : PubMed/NCBI
18	Rotondo R, Mastracci L, Piazza T, Barisione G, Fabbi M, Cassanello M, Costa R, Morandi B, Astigiano S, Cesario A, et al: Arginase 2 is expressed by human lung cancer, but it neither induces immune suppression, nor affects disease progression. Int J Cancer. 123:1108–1116. 2008. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Jochems C and Schlom J: Tumor-infiltrating immune cells and prognosis: The potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood). 236:567–579. 2011. View Article : Google Scholar : PubMed/NCBI
21	Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C and Iacopetta B: Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 27:186–192. 2009. View Article : Google Scholar : PubMed/NCBI
22	Di Giorgio A, Botti C, Tocchi A, Mingazzini P and Flammia M: The influence of tumor lymphocytic infiltration on long term survival of surgically treated colorectal cancer patients. Int Surg. 77:256–260. 1992.PubMed/NCBI
23	Nzula S, Going JJ and Stott DI: Antigen-driven clonal proliferation, somatic hypermutation, and selection of B lymphocytes infiltrating human ductal breast carcinomas. Cancer Res. 63:3275–3280. 2003.PubMed/NCBI
24	Biswas SK and Mantovani A: Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nat Immunol. 11:889–896. 2010. View Article : Google Scholar : PubMed/NCBI
25	Fleetwood AJ, Lawrence T, Hamilton JA and Cook AD: Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: Implications for CSF blockade in inflammation. J Immunol. 178:5245–5252. 2007. View Article : Google Scholar : PubMed/NCBI
26	Gordon S and Martinez FO: Alternative activation of macrophages: Mechanism and functions. Immunity. 32:593–604. 2010. View Article : Google Scholar : PubMed/NCBI
27	Mantovani A, Sica A and Locati M: Macrophage polarization comes of age. Immunity. 23:344–346. 2005. View Article : Google Scholar : PubMed/NCBI
28	Martinez FO, Gordon S, Locati M and Mantovani A: Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: New molecules and patterns of gene expression. J Immunol. 177:7303–7311. 2006. View Article : Google Scholar : PubMed/NCBI
29	Martinez FO, Helming L and Gordon S: Alternative activation of macrophages: An immunologic functional perspective. Annu Rev Immunol. 27:451–483. 2009. View Article : Google Scholar : PubMed/NCBI
30	Stein M, Keshav S, Harris N and Gordon S: Interleukin 4 potently enhances murine macrophage mannose receptor activity: A marker of alternative immunologic macrophage activation. J Exp Med. 176:287–292. 1992. View Article : Google Scholar : PubMed/NCBI
31	Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, Hussell T, Feldmann M and Udalova IA: IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol. 12:231–238. 2011. View Article : Google Scholar : PubMed/NCBI
32	Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T, et al: The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol. 11:936–944. 2010. View Article : Google Scholar : PubMed/NCBI
33	Brunschwig A: The Efficacy of ‘Coley's Toxin’ in the Treatment of Sarcoma: An experimental study. Ann Surg. 109:109–113. 1939. View Article : Google Scholar : PubMed/NCBI
34	Maletzki C, Klier U, Obst W, Kreikemeyer B and Linnebacher M: Reevaluating the concept of treating experimental tumors with a mixed bacterial vaccine: Coley's toxin. Clin Dev Immunol. 2012:2306252012. View Article : Google Scholar : PubMed/NCBI
35	Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L, Wei S, Crespo J, Wan S, Vatan L, et al: Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol. 17:95–103. 2016. View Article : Google Scholar : PubMed/NCBI
36	Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, et al: Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 527:249–253. 2015. View Article : Google Scholar : PubMed/NCBI