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Original Research

Immunological differences between colorectal cancer and normal mucosa uncover a prognostically relevant immune cell profile

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Article: e1537693 | Received 24 Jun 2018, Accepted 10 Oct 2018, Published online: 05 Nov 2018

References

  • Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2018;68(1):7–30. doi:10.3322/caac.21442.
  • Augestad KM, Merok MA, Ignatovic D. Tailored treatment of colorectal cancer: surgical, molecular, and genetic considerations. Clin Med Insights Oncol. 2017;11. doi:10.1177/1179554917690766.
  • Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, Van de Velde CJ, Balmana J, Regula J, et al. Esmo consensus guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol. 2012;23(10):2479–2516. doi:10.1093/annonc/mds236.
  • Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura A, Ohtani H. CD8(+) T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58(16):3491–3494.
  • Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960−1964. doi:10.1126/science.1129139.
  • Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, Bruneval P, Trajanoski Z, Fridman W-H-H, Pagès F, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29(6):610–618. doi:10.1200/JCO.2010.30.5425.
  • Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443−2454. doi:10.1056/NEJMoa1200690.
  • Markman JL, Shiao SL. Impact of the immune system and immunotherapy in colorectal cancer. J Gastrointest Oncol. 2015;6(2):208–223. doi:10.3978/j.issn.2078-6891.2014.077.
  • Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, Blosser RL, Fan H, Wang H, Luber BS, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5:43−51. doi:10.1158/2159-8290.CD-14-0863.
  • Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov. 2015;5(1):16–18. doi:10.1158/2159-8290.CD-14-1397.
  • Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014;14:141−153. doi:10.1038/nri3608.
  • Norton SE, Dunn ETJ, McCall JL, Munro F, Kemp RA. Gut macrophage phenotype is dependent on the tumor microenvironment in colorectal cancer. Clin Transl Immunol. 2016;5(4):e76. doi:10.1038/cti.2016.21.
  • Edin S, Wikberg ML, Dahlin AM, Rutegård J, Öberg Å, Oldenborg P-A-A, Palmqvist R, Rutegard J, Oberg A, Oldenborg P-A-A, et al. The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One. 2012;7(10):e47045. doi:10.1371/journal.pone.0047045.
  • Ålgars A, Irjala H, Vaittinen S, Huhtinen H, Sundström J, Salmi M, Ristamäki R, Jalkanen S. Type and location of tumor-infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients. Int J Cancer. 2012;131(4):864–873. doi:10.1002/ijc.26457.
  • Marech I, Ammendola M, Sacco R, Sammarco G, Zuccalà V, Zizzo N, Leporini C, Luposella M, Patruno R, Filippelli G, et al. Tumour-associated macrophages correlate with microvascular bed extension in colorectal cancer patients. J Cell Mol Med. 2016;20(7):1373–1380. doi:10.1111/jcmm.12826.
  • Gulubova M, Ananiev J, Yovchev Y, Julianov A, Karashmalakov A, Vlaykova T. The density of macrophages in colorectal cancer is inversely correlated to TGF-β1 expression and patients’ survival. J Mol Histol. 2013;44:679–692. doi:10.1007/s10735-013-9520-9.
  • Koelzer VH, Canonica K, Dawson H, Sokol L, Karamitopoulou-Diamantis E, Lugli A, Zlobec I. Phenotyping of tumor-associated macrophages in colorectal cancer: impact on single cell invasion (tumor budding) and clinicopathological outcome. Oncoimmunology. 2016;5(4):1−10. doi:10.1080/2162402X.2015.1106677.
  • Cheroutre H, Lambolez F, Mucida D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol. 2011;11(7):445–456. doi:10.1038/nri3007.
  • Shires J, Theodoridis E, Hayday AC. Biological insights into TCR gamma delta+ and TCR alpha beta+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity. 2001;15:419–434. doi:10.1016/S1074-7613(01)00192-3.
  • Pinchuk IV, Saada JI, Beswick EJ, Boya G, Qiu SM, Mifflin RC, Raju GS, Reyes VE, Powell DW. PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity. Gastroenterology. 2008;135:1228–1237. doi:10.1053/j.gastro.2008.07.016.
  • Koch M, Beckhove P, Den WJ, Autenrieth D, Wagner P, Nummer D, Specht S, Antolovic D, Galindo L, Schmitz-Winnenthal FH, et al. Tumor infiltrating T lymphocytes in colorectal cancer. Ann Surg. 2006;244(6):986−993. doi:10.1097/01.sla.0000247058.43243.7b.
  • Sinicrope FA, Rego RL, Ansell SM, Knutson KL, Foster NR, Sargent DJ. Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology. 2009;137:1270–1279. doi:10.1053/j.gastro.2009.06.053.
  • Zhang X, Kelaria S, Kerstetter J, Wang J. The functional and prognostic implications of regulatory T cells in colorectal carcinoma. J Gastrointest Oncol. 2015;6(3):307–313. doi:10.3978/j.issn.2078-6891.2015.017.
  • Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, Maeda Y, Hamaguchi M, Ohkura N, Sato E, et al. Two FOXP3+CD4+ T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med. 2016;22(6):679–684. doi:10.1038/nm.4086.
  • Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27(1):109–118. doi:10.1038/cr.2016.151.
  • Ziegler SF, Ramsdell F, Alderson MR. The activation antigen CD69. Stem Cells. 1994;12:456−465. doi:10.1002/stem.5530120502.
  • Elkord E, Abd Al Samid M, Chaudhary B. Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP. Oncotarget. 2015;6(24):20026−20036. doi:10.18632/oncotarget.4771.
  • Gu J, Ni X, Pan X, Lu H, Lu Y, Zhao J, Guo Zheng S, Hippen KL, Wang X, Lu L. Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions. Cell Mol Immunol. 2017;14(6):521−528. doi:10.1038/cmi.2016.30.
  • Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, Wu X, Vo HT, Ma XJ, Luo Y. RNAscope: A novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012;14(1):22–29. doi:10.1016/j.jmoldx.2011.08.002.
  • Bain CC, Scott CL, Uronen-Hansson H, Gudjonsson S, Jansson O, Grip O, Guilliams M, Malissen B, Agace WW, Mowat AM. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 2013;6(3):498–510. doi:10.1038/mi.2012.89.
  • Bernardo D, Marin AC, Fernández-Tomé S, Montalban-Arques A, Carrasco A, Tristán E, Ortega-Moreno L, Mora-Gutiérrez I, Díaz-Guerra A, Caminero-Fernández R, et al. Human intestinal pro-inflammatory CD11chighCCR2+CX3CR1+ macrophages, but not their tolerogenic CD11c−CCR2−CX3CR1− counterparts, are expanded in inflammatory bowel disease. Mucosal Immunol. 2018;11:1114–1126. doi:10.1038/s41385-018-0030-7.
  • Bujko A, Atlasy N, Landsverk OJB, Richter L, Yaqub S, Horneland R, Øyen O, Aandahl EM, Aabakken L, Stunnenberg HG, et al. Transcriptional and functional profiling defines human small intestinal macrophage subsets. J Exp Med. 2018;215(2):441–458. doi:10.1084/jem.20170057.
  • The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–337. doi:10.1038/nature11252.
  • Mlecnik B, Bindea G, Kirilovsky A, Angell HK, Obenauf AC, Tosolini M, Church SE, Maby P, Vasaturo A, Angelova M, et al. The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med. 2016;8(327):1−14. doi:10.1126/scitranslmed.aad6352.
  • Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, Marisa L, Roepman P, Nyamundanda G, Angelino P, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–1356. doi:10.1038/nm.3967.
  • Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pagès F, et al. 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(4):1263–1271. doi:10.1158/0008-5472.CAN-10-2907.
  • Beswick EJ, Johnson JR, Saada JI, House J, Dann S, Qiu S, Allan R, Powell DW, Reyes VE, Irina V. TLR4 activation enhances the PD-L1 − mediated tolerogenic capacity of colonic CD90 + stromal cells. J Immunol. 2014;193:2218–2229. doi:10.4049/jimmunol.1203441.
  • Beswick EJ, Grim C, Singh A, Aguirre JE, Tafoya M, Pinchuk IV. Expression of programmed death-ligand 1 by human colonic CD90+ stromal cells differs between ulcerative colitis and Crohn’s disease and determines their capacity to suppress Th1 cells. Front Immunol. 2018;9:1125. doi:10.3389/fimmu.2018.01125.
  • Nava P, Koch S, Laukoetter MG, Lee WY, Kolegraff K, Capaldo CT, Beeman N, Addis C, Gerner-Smidt K, Neumaier I, et al. Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. Immunity. 2010;32(3):392−402. doi:10.1016/j.immuni.2010.03.001.
  • Naschberger E, Croner RS, Merkel S, Dimmler A, Tripal P, Amann KU, Kremmer E, Brueckl WM, Papadopoulos T, Hohenadl C, et al. Angiostatic immune reaction in colorectal carcinoma: impact on survival and perspectives for antiangiogenic therapy. Int J Cancer. 2008;123(9):2120–2129. doi:10.1002/ijc.23764.
  • Grenz S, Naschberger E, Merkel S, Britzen-Laurent N, Schaal U, Konrad A, Aigner M, Rau TT, Hartmann A, Croner RS, et al. IFN-γ-driven intratumoral microenvironment exhibits superior prognostic effect compared with an IFN-α-driven microenvironment in patients with colon carcinoma. Am J Pathol. 2013;183(6):1897–1909. doi:10.1016/j.ajpath.2013.08.025.
  • Wang L, Wang Y, Song Z, Chu J, Qu X. Deficiency of interferon-gamma or its receptor promotes colorectal cancer development. J Interf Cytokine Res. 2015;35(4):273−280. doi:10.1089/jir.2014.0132.
  • Wang Z, Hong J, Sun W, Xu G, Li N, Chen X, Liu A, Xu L, Sun B, Zhang JZ. Role of IFN-γ in induction of Foxp3 and conversion of CD4+CD25– T cells to CD4+ Tregs. J Clin Invest. 2006;116(9):2434–2441. doi:10.1172/JCI25826.2434.
  • Shang B, Liu Y, Jiang S, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5(1):15179. doi:10.1038/srep15179.
  • Berntsson J, Svensson MC, Leandersson K, Nodin B, Micke P, Larsson AH, Eberhard J, Jirström K. The clinical impact of tumour-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite: a cohort study. Int J Cancer. 2017;141:1654–1666. doi:10.1002/ijc.30869.
  • Scurr M, Ladell K, Besneux M, Christian A, Hockey T, Smart K, Bridgeman H, Hargest R, Phillips S, Davies M, et al. Highly prevalent colorectal cancer-infiltrating LAP+ Foxp3− T cells exhibit more potent immunosuppressive activity than Foxp3+ regulatory T cells. Mucosal Immunol. 2014;7(2):428−439. doi:10.1038/mi.2013.62.
  • Rodríguez-Perea AL, Arcia ED, Rueda CM, Velilla PA. Phenotypical characterization of regulatory T cells in humans and rodents. Clin Exp Immunol. 2016;185(3):281–291. doi:10.1111/cei.12804.
  • Sundström P, Stenstad H, Langenes V, Ahlmanner F, Theander L, Ndah TG, Fredin K, Borjesson L, Gustavsson B, Bastid J, et al. Regulatory T cells from colon cancer patients inhibit effector T-cell migration through an adenosine-dependent mechanism. Cancer Immunol Res. 2016;4(3):183−193. doi:10.1158/2326-6066.CIR-15-0050.
  • Nakanishi Y, Ikebuchi R, Chtanova T, Kusumoto Y, Okuyama H, Moriya T, Honda T, Kabashima K, Watanabe T, Sakai Y, et al. Regulatory T cells with superior immunosuppressive capacity emigrate from the inflamed colon to draining lymph nodes. Mucosal Immunol. 2017 Aug 2. doi:10.1038/mi.2017.64.
  • Sathaliyawala T, Kubota M, Yudanin N, Turner D, Camp P, Thome JJC, Bickham KL, Lerner H, Goldstein M, Sykes M, et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity. 2013;38(1):187–197. doi:10.1016/j.immuni.2012.09.020.
  • Cibrián D, Sánchez-Madrid F. CD69: from activation marker to metabolic gatekeeper. Eur J Immunol. 2017;47(6):946–953. doi:10.1002/eji.201646837.
  • Marazuela M, García-López MA, Figueroa-Vega N, de la Fuente H, Alvarado-Sánchez B, Monsiváis-Urenda A, Sánchez-Madrid F, González-Amaro R. Regulatory T cells in human autoimmune thyroid disease. J Clin Endocrinol Metab. 2006;91(9):3639–3646. doi:10.1210/jc.2005-2337.
  • Radulovic K, Niess JH. CD69 is the crucial regulator of intestinal inflammation: a new target molecule for IBD treatment? J Immunol Res. 2015;2015:1–12. doi:10.1155/2015/497056.
  • Konkel JE, Chen W. Balancing acts: the role of TGF-beta in the mucosal immune system. Trends Mol Med. 2011;17(11):668–676. doi:10.1016/j.molmed.2011.07.002.
  • Perussia B, Dayton ET, Lazarus R, Fanning V, Trinchieri G. Immune interferon induces the receptor for monomeric IgG1 on human monocytic and myeloid cells. J Exp Med. 1983;158:1092–1113. doi:10.1084/jem.158.4.1092.
  • Kamada N, Hisamatsu T, Okamoto S, Chinen H, Kobayashi T, Sato T, Sakuraba A, Kitazume MT, Sugita A, Koganei K, et al. Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis. J Clin Invest. 2008;118(6):2269–2280. doi:10.1172/JCI34610DS1.
  • Ramos MV, Fernández GC, Brando RJF, Panek CA, Bentancor LV, Landoni VI, Isturiz MA, Palermo MS. Interleukin-10 and interferon-γ modulate surface expression of fractalkine-receptor (CX3CR1) via PI3K in monocytes. Immunology. 2010;129:600–609. doi:10.1111/j.1365-2567.2009.03181.x.
  • Bögels M, Braster R, Nijland PG, Gü N, van de Luijtgaarden W, Fijneman RJA, Meijer GA, Jimenez CR, Beelen RHJ, van Egmond M. Carcinoma origin dictates differential skewing of monocyte function. Oncoimmunology. 2012;1(6):798–809. doi:10.4161/onci.20427.
  • Ong SM, Tan YC, Beretta O, Jiang D, Yeap WH, Tai JJYY, Wong WC, Yang H, Schwarz H, Lim KH, et al. Macrophages in human colorectal cancer are pro-inflammatory and prime T cells towards an anti-tumour type-1 inflammatory response. Eur J Immunol. 2012;42(1):89–100. doi:10.1002/eji.201141825.
  • Harada K, Dong X, Estrella JS, Correa AM, Xu Y, Hofstetter WL, Sudo K, Onodera H, Suzuki K, Suzuki A, et al. Tumor-associated macrophage infiltration is highly associated with PD-L1 expression in gastric adenocarcinoma. Gastric Cancer. 2018;21:31–40. doi:10.1007/s10120-017-0760-3.
  • Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 2001;22(5):265–268. doi:10.1016/S1471-4906(01)01888-9.
  • Arce Vargas F, Furness AJS, Solomon I, Joshi K, Mekkaoui L, Lesko MH, Miranda Rota E, Dahan R, Georgiou A, Sledzinska A, et al. Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity. 2017;46(4):577–586. doi:10.1016/j.immuni.2017.03.013.
  • Brahmer, Julie; Tykodi, Scott; Chow L, Hwu W, Ph D, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–2465.
  • Wan YW, Allen GI, Anderson ML, Liu Z. TCGA2STAT: simple TCGA data access for integrated statistical analysis in R. R package version 1.2. Bioinformatics. 2015;32(6):952–954. doi:10.1093/bioinformatics/btv677.
  • Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47. doi:10.1093/nar/gkv007.
  • R Core Team. R: a language and environment for statistical computing. R Found Stat Comput. 2017;1(2.11.1):409. doi:10.1007/978-3-540-74686-7.
  • Venables WN, Ripley BD. Modern applied statistics with S. Technometrics. 2003;45(1):111. doi:10.1198/tech.2003.s33.