Inflammation Research

, Volume 67, Issue 5, pp 375–389 | Cite as

Evolving notions on immune response in colorectal cancer and their implications for biomarker development

  • Fabio Grizzi
  • Gianluca Basso
  • Elena Monica Borroni
  • Tommaso Cavalleri
  • Paolo Bianchi
  • Sanja Stifter
  • Maurizio Chiriva-Internati
  • Alberto Malesci
  • Luigi Laghi



Colorectal cancer (CRC) still represents the third most commonly diagnosed type of cancer in men and women worldwide. CRC is acknowledged as a heterogeneous disease that develops through a multi-step sequence of events driven by clonal selections; this observation is sustained by the fact that histologically similar tumors may have completely different outcomes, including a varied response to therapy.


In “early” and “intermediate” stage of CRC (stages II and III, respectively) there is a compelling need for new biomarkers fit to assess the metastatic potential of their disease, selecting patients with aggressive disease that might benefit from adjuvant and targeted therapies. Therefore, we review the actual notions on immune response in colorectal cancer and their implications for biomarker development.


The recognition of the key role of immune cells in human cancer progression has recently drawn attention on the tumor immune microenvironment, as a source of new indicators of tumor outcome and response to therapy. Thus, beside consolidated histopathological biomarkers, immune endpoints are now emerging as potential biomarkers.


The introduction of immune signatures and cellular and molecular components of the immune system as biomarkers is particularly important considering the increasing use of immune-based cancer therapies as therapeutic strategies for cancer patients.


Colorectal cancer Immunity Macrophages T-lymphocytes Chemokines Biomarkers Prognosis 


Author contributions

GF, BG, BEM, CT, BP, SS, CIM, MA, and LL draft discuss the manuscript and approved the final version.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. 1.
    Welch HG, Robertson DJ. Colorectal cancer on the decline—why screening can’t explain it all. N Engl J Med. 2016;374:1605–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Keane MG, Johnson GJ. Early diagnosis improves survival in colorectal cancer. Pract 2012;256:15–18.Google Scholar
  3. 3.
    Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin. 2012;62:10–29.PubMedCrossRefGoogle Scholar
  4. 4.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–E386.PubMedCrossRefGoogle Scholar
  5. 5.
    Abdelsattar ZM, Wong SL, Regenbogen SE, Jomaa DM, Hardiman KM, Hendren S. Colorectal cancer outcomes and treatment patterns in patients too young for average-risk screening. Cancer. 2016;122:929–34.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Choe EK, Kim D, Kim HJ, Park KJ. Association of visceral obesity and early colorectal neoplasia. WJG. 2013;19:8349–56.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.PubMedCrossRefGoogle Scholar
  8. 8.
    Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.CrossRefGoogle Scholar
  9. 9.
    Ilyas M, Tomlinson IP. Genetic pathways in colorectal cancer. Histopathology. 1996;28:389–99.CrossRefGoogle Scholar
  10. 10.
    Walther A, Johnstone E, Swanton C, Midgley R, Tomlinson I, Kerr D. Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer. 2009;9:489–99.CrossRefGoogle Scholar
  11. 11.
    Sugihara Y, Taniguchi H, Kushima R, Tsuda H, Kubota D, Ichikawa H, et al. Laser microdissection and two-dimensional difference gel electrophoresis reveal proteomic intra-tumor heterogeneity in colorectal cancer. J Proteom. 2013;78:134–47.CrossRefGoogle Scholar
  12. 12.
    Vogelstein B, Kinzler KW. The multistep nature of cancer. TIG. 1993;9:138–41.CrossRefGoogle Scholar
  13. 13.
    Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol. 2012;27:1423–31.PubMedCrossRefGoogle Scholar
  14. 14.
    Grizzi F, Celesti G, Basso G, Laghi L. Tumor budding as a potential histopathological biomarker in colorectal cancer: hype or hope? WJG. 2012;18:6532–6.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    George B, Kopetz S. Predictive and prognostic markers in colorectal cancer. Curr Oncol Rep. 2011;13:206–15.CrossRefGoogle Scholar
  16. 16.
    Kelley RK, Venook AP. Prognostic and predictive markers in stage II colon cancer: is there a role for gene expression profiling? Clin Colorect Cancer. 2011;10:73–80.CrossRefGoogle Scholar
  17. 17.
    Hrasovec S, Glavac D. MicroRNAs as Novel Biomarkers in Colorectal Cancer. Front Genet. 2012;3:180.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Malesci A, Laghi L, Bianchi P, Delconte G, Randolph A, Torri V, et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res. 2007;13:3831–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Sinicrope FA, Foster NR, Thibodeau SN, Marsoni S, Monges G, Labianca R, et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 2011;103:863–75.CrossRefGoogle Scholar
  20. 20.
    Andre T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to braf mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015;33:4176–87.PubMedCrossRefGoogle Scholar
  21. 21.
    Laghi L, Bianchi P, Malesci A. Differences and evolution of the methods for the assessment of microsatellite instability. Oncogene. 2008;27:6313–21.PubMedCrossRefGoogle Scholar
  22. 22.
    Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248–57.PubMedGoogle Scholar
  23. 23.
    Yashiro M, Laghi L, Saito K, Carethers JM, Slezak P, Rubio C, et al. Serrated adenomas have a pattern of genetic alterations that distinguishes them from other colorectal polyps. Cancer Epidemiol Biomark. 2005;14:2253–6.CrossRefGoogle Scholar
  24. 24.
    Jass JR. Molecular heterogeneity of colorectal cancer: implications for cancer control. Surg Oncol. 2007;16(Suppl 1):S7–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011;42:1–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Kriegl L, Vieth M, Kirchner T, Menssen A. Up-regulation of c-MYC and SIRT1 expression correlates with malignant transformation in the serrated route to colorectal cancer. Oncotarget. 2012;3:1182–93.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Gaiser T, Meinhardt S, Hirsch D, Killian JK, Gaedcke J, Jo P, et al. Molecular patterns in the evolution of serrated lesion of the colorectum. Int J Cancer Journal international du cancer. 2013;132:1800–10.PubMedCrossRefGoogle Scholar
  28. 28.
    Pino MS, Kikuchi H, Zeng M, Herraiz MT, Sperduti I, Berger D, et al. Epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability. Gastroenterology. 2010;138:1406–17.PubMedCrossRefGoogle Scholar
  29. 29.
    Celesti G, Di Caro G, Bianchi P, Grizzi F, Basso G, Marchesi F, et al. Presence of Twist1-positive neoplastic cells in the stroma of chromosome-unstable colorectal tumors. Gastroenterology. 2013;145:647–57 (e15).CrossRefGoogle Scholar
  30. 30.
    Taube JM, Galon J, Sholl LM, Rodig SJ, Cottrell TR, Giraldo NA, et al. Implications of the tumor immune microenvironment for staging and therapeutics. Modern Pathol. 2017.
  31. 31.
    Kronenberg M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol. 2005;23:877–900.PubMedCrossRefGoogle Scholar
  32. 32.
    Kistner L, Doll D, Holtorf A, Nitsche U, Janssen KP. Interferon-inducible CXC-chemokines are crucial immune modulators and survival predictors in colorectal cancer. Oncotarget. 2017;8:89998–90012.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, et al. CD3+ cells at the invasive margin of deeply invading (pT3–T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncol. 2009;10:877–84.CrossRefGoogle Scholar
  34. 34.
    Malesci A, Bianchi P, Celesti G, Basso G, Marchesi F, Grizzi F, et al. Tumor-associated macrophages and response to 5-fluorouracil adjuvant therapy in stage III colorectal cancer. Oncoimmunology. 2017;6:e1342918.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, et al. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol. 2014;232:199–209.PubMedCrossRefGoogle Scholar
  37. 37.
    Galon J, Pages F, Marincola FM, Angell HK, Thurin M, Lugli A, et al. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med. 2012;10:205.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Mlecnik B, Bindea G, Angell HK, Maby P, Angelova M, Tougeron D, et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity. 2016;44:698–711.PubMedCrossRefGoogle Scholar
  39. 39.
    Gao P, Zhou X, Wang ZN, Song YX, Tong LL, Xu YY, et al. Which is a more accurate predictor in colorectal survival analysis? Nine data mining algorithms vs. the TNM staging system. PloS One. 2012;7:e42015.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Malesci A, Laghi L. Novel prognostic biomarkers in colorectal cancer. Digest Dis. 2012;30:296–303.CrossRefGoogle Scholar
  41. 41.
    Shia J, Klimstra DS, Bagci P, Basturk O, Adsay NV. TNM staging of colorectal carcinoma: issues and caveats. Semin Diagn Pathol. 2012;29:142–53.CrossRefGoogle Scholar
  42. 42.
    Ueno H, Mochizuki H, Akagi Y, Kusumi T, Yamada K, Ikegami M, et al. Optimal colorectal cancer staging criteria in TNM classification. J Clin Oncol. 2012;30:1519–26.PubMedCrossRefGoogle Scholar
  43. 43.
    Kim MJ, Jeong SY, Choi SJ, Ryoo SB, Park JW, Park KJ, et al. Survival paradox between stage IIB/C (T4N0) and stage IIIA (T1–2N1) colon cancer. Ann Surg Oncol. 2015;22:505–12.Google Scholar
  44. 44.
    Puppa G, Sonzogni A, Colombari R, Pelosi G. TNM staging system of colorectal carcinoma: a critical appraisal of challenging issues. Arch Pathol Lab Med. 2010;134:837–52.Google Scholar
  45. 45.
    Sinicrope FA, Shi Q. Combining molecular markers with the TNM staging system to improve prognostication in stage II and III colon cancer: are we ready yet? J Natl Cancer I. 2012;104:1616–8.CrossRefGoogle Scholar
  46. 46.
    Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncol. 2010;15:699–731.Google Scholar
  47. 47.
    Mandrekar SJ, Sargent DJ. Design of clinical trials for biomarker research in oncology. Clin Investig. 2011;1:1629–36.CrossRefGoogle Scholar
  48. 48.
    Butterfield LH, Palucka AK, Britten CM, Dhodapkar MV, Hakansson L, Janetzki S, et al. Recommendations from the iSBTc-SITC/FDA/NCI workshop on immunotherapy biomarkers. Clin Cancer Res. 2011;17:3064–76.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    de Wit M, Fijneman RJ, Verheul HM, Meijer GA, Jimenez CR. Proteomics in colorectal cancer translational research: biomarker discovery for clinical applications. Clin Biochem. 2013;46:466–79.Google Scholar
  50. 50.
    Mathivanan S, Ji H, Tauro BJ, Chen YS, Simpson RJ. Identifying mutated proteins secreted by colon cancer cell lines using mass spectrometry. J Proteom. 2012;76(Spec No.):141–9.CrossRefGoogle Scholar
  51. 51.
    Peng Y, Li X, Wu M, Yang J, Liu M, Zhang W, et al. New prognosis biomarkers identified by dynamic proteomic analysis of colorectal cancer. Mol bioSyst. 2012;8:3077–88.PubMedCrossRefGoogle Scholar
  52. 52.
    Berg M, Soreide K. Genetic and epigenetic traits as biomarkers in colorectal cancer. Int J Mol Sci. 2011;12:9426–39.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Church D, Midgley R, Kerr D. Biomarkers in early-stage colorectal cancer: ready for prime time? Digest Dis. 2012;30(Suppl 2):27–33.CrossRefGoogle Scholar
  54. 54.
    Legolvan MP, Taliano RJ, Resnick MB. Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach. Hum Pathol. 2012;43:1157–68.PubMedCrossRefGoogle Scholar
  55. 55.
    Sanz-Pamplona R, Berenguer A, Cordero D, Riccadonna S, Sole X, Crous-Bou M, et al. Clinical value of prognosis gene expression signatures in colorectal cancer: a systematic review. PloS One. 2012;7:e48877.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Benson AB 3rd, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22:3408–19.PubMedCrossRefGoogle Scholar
  57. 57.
    Gill S, Loprinzi CL, Sargent DJ, Thome SD, Alberts SR, Haller DG, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol. 2004;22:1797–806.CrossRefGoogle Scholar
  58. 58.
    McMillan DC, McArdle CS, Morrison DS. A clinical risk score to predict 3-, 5- and 10-year survival in patients undergoing surgery for Dukes B colorectal cancer. Br J Cancer. 2010;103:970–4.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Dotan E, Cohen SJ. Challenges in the management of stage II colon cancer. Semin Oncol. 2011;38:511–20.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Malesci A, Basso G, Bianchi P, Fini L, Grizzi F, Celesti G, et al. Molecular heterogeneity and prognostic implications of synchronous advanced colorectal neoplasia. Br J Cancer. 2014;110:1228–35.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Nosho K, Kure S, Irahara N, Shima K, Baba Y, Spiegelman D, et al. A prospective cohort study shows unique epigenetic, genetic, and prognostic features of synchronous colorectal cancers. Gastroenterology. 2009;137:1609–20 e1-3.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Cereda M, Gambardella G, Benedetti L, Iannelli F, Patel D, Basso G, et al. Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes. Nat Commun. 2016;7:12072.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Cowin PA, Anglesio M, Etemadmoghadam D, Bowtell DD. Profiling the cancer genome. Annu Rev Genom Hum Genet. 2010;11:133–59.CrossRefGoogle Scholar
  64. 64.
    Bustin SA, Murphy J. RNA biomarkers in colorectal cancer. Methods. 2013;59:116–25.CrossRefGoogle Scholar
  65. 65.
    Deschoolmeester V, Boeckx C, Baay M, Weyler J, Wuyts W, Van Marck E, et al. KRAS mutation detection and prognostic potential in sporadic colorectal cancer using high-resolution melting analysis. Br J Cancer. 2010;103:1627–36.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Ren JJ, Li GX, Ge J, Li X, Zhao YS. Is K-ras gene mutation a prognostic factor for colorectal cancer: a systematic review and meta-analysis. Dis Colon Rectum. 2012;55:913–23.PubMedCrossRefGoogle Scholar
  67. 67.
    Ogino S, Shima K, Meyerhardt JA, McCleary NJ, Ng K, Hollis D, et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res. 2012;18:890–900.PubMedCrossRefGoogle Scholar
  68. 68.
    Laghi L, Malesci A. Microsatellite instability and therapeutic consequences in colorectal cancer. Dig Dis. 2012;30:304–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E. Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer. 2010;46:2788–98.PubMedCrossRefGoogle Scholar
  70. 70.
    Merok MA, Ahlquist T, Royrvik EC, Tufteland KF, Hektoen M, Sjo OH, et al. Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series. Ann Oncol. 2013;24:1274–82.PubMedCrossRefGoogle Scholar
  71. 71.
    Sinicrope FA, Sargent DJ. Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications. Clin Cancer Res. 2012;18:1506–12.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Laghi L, Bianchi P, Roncalli M, Malesci A. Re. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:1402–3 (author reply 1403–4).PubMedCrossRefGoogle Scholar
  73. 73.
    Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.PubMedCrossRefGoogle Scholar
  74. 74.
    Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology. 2014;147:502–26.CrossRefGoogle Scholar
  75. 75.
    Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MWY, et al. Hereditary colorectal cancer syndromes: American society of clinical oncology clinical practice guideline endorsement of the familial risk–colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 2015;33:209–17.PubMedCrossRefGoogle Scholar
  76. 76.
    Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, et al. Modulation of mismatch repair and genomic stability by miR-155. Proc Natl Acad Sci USA. 2010;107:6982–7.Google Scholar
  77. 77.
    Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, et al. MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci USA. 2010;107:21098–103.Google Scholar
  78. 78.
    Moshayoff V, Faktor O, Laghi L, Celesti G, Peretz T, Keret D, et al. Feasibility of unbiased RNA profiling of colorectal tumors: a proof of principle. PloS One. 2016;11:e0159522.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21:795–801.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Bindea G, Mlecnik B, Fridman WH, Galon J. The prognostic impact of anti-cancer immune response: a novel classification of cancer patients. Semin Immunopathol. 2011;33:335–40.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Zlobec I, Koelzer VH, Dawson H, Perren A, Lugli A. Next-generation tissue microarray (ngTMA) increases the quality of biomarker studies: an example using CD3, CD8, and CD45RO in the tumor microenvironment of six different solid tumor types. J Transl Med. 2013;11:104.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Mariani F, Sena P, Roncucci L. Inflammatory pathways in the early steps of colorectal cancer development. WJG. 2014;20:9716–31.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Coppola A, Arriga R, Lauro D, Del Principe MI, Buccisano F, Maurillo L, et al. NK cell inflammation in the clinical outcome of colorectal carcinoma. Front Med. 2015;2:33.CrossRefGoogle Scholar
  84. 84.
    Shunyakov L, Ryan CK, Sahasrabudhe DM, Khorana AA. The influence of host response on colorectal cancer prognosis. Clin Colorect Cancer. 2004;4:38–45.CrossRefGoogle Scholar
  85. 85.
    Titu LV, Monson JR, Greenman J. The role of CD8(+) T cells in immune responses to colorectal cancer. CII. 2002;51:235–47.Google Scholar
  86. 86.
    Dalerba P, Maccalli C, Casati C, Castelli C, Parmiani G. Immunology and immunotherapy of colorectal cancer. Crit Rev Oncol Hemat. 2003;46:33–57.CrossRefGoogle Scholar
  87. 87.
    Scurr M, Gallimore A, Godkin A. T cell subsets and colorectal cancer: discerning the good from the bad. Cell Immunol. 2012;279:21–4.PubMedCrossRefGoogle Scholar
  88. 88.
    Whiteside TL. What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol. 2012;22:327–34.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Whiteside TL, Schuler P, Schilling B. Induced and natural regulatory T cells in human cancer. Expert Opin Biol Ther. 2012;12:1383–97.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307.PubMedCrossRefGoogle Scholar
  91. 91.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.PubMedCrossRefGoogle Scholar
  92. 92.
    Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.PubMedCrossRefGoogle Scholar
  93. 93.
    Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. 2001;158:527–35.CrossRefGoogle Scholar
  94. 94.
    Graham DM, Appelman HD. Crohn’s-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Modern Pathol. 1990;3:332–5.Google Scholar
  95. 95.
    Aloisi F, Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol. 2006;6:205–17.PubMedCrossRefGoogle Scholar
  96. 96.
    Carragher DM, Rangel-Moreno J, Randall TD. Ectopic lymphoid tissues and local immunity. Semin Immunol. 2008;20:26–42.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Bergomas F, Grizzi F, Doni A, Pesce S, Laghi L, Allavena P, et al. Tertiary intratumor lymphoid tissue in colo-rectal cancer. Cancers. 2011;4:1–10.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L. The origin and function of tumor-associated macrophages. Immunol Today. 1992;13:265–70.CrossRefGoogle Scholar
  99. 99.
    Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010;22:231–7.PubMedCrossRefGoogle Scholar
  101. 101.
    Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–96.PubMedCrossRefGoogle Scholar
  102. 102.
    Mantovani A, Romero P, Palucka AK, Marincola FM. Tumour immunity: effector response to tumour and role of the microenvironment. Lancet. 2008;371:771–83.CrossRefGoogle Scholar
  103. 103.
    Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239–52.PubMedCrossRefGoogle Scholar
  104. 104.
    Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8:618–31.PubMedCrossRefGoogle Scholar
  105. 105.
    Allavena P, Sica A, Garlanda C, Mantovani A. The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev. 2008;222:155–61.PubMedCrossRefGoogle Scholar
  106. 106.
    Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappa B and enhanced IRF-3/STAT1 activation). Blood. 2006;107:2112–22.PubMedCrossRefGoogle Scholar
  107. 107.
    Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, Zammataro L, et al. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J Immunol. 2010;185:642–52.PubMedCrossRefGoogle Scholar
  108. 108.
    Mantovani A, Peri G, Polentarutti N, Bolis G, Mangioni C, Spreafico F. Effects on in vitro tumor growth of macrophages isolated from human ascitic ovarian tumors. Int J Cancer Journal international du cancer. 1979;23:157–64.Google Scholar
  109. 109.
    Mantovani A, Allavena P, Sessa C, Bolis G, Mangioni C. Natural killer activity of lymphoid cells isolated from human ascitic ovarian tumors. Int J Cancer Journal international du cancer. 1980;25:573–82.Google Scholar
  110. 110.
    Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res. 2007;13:1472–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun WJ, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612–6.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Parcesepe P, Giordano G, Laudanna C, Febbraro A, Pancione M. Cancer-associated immune resistance and evasion of immune surveillance in colorectal cancer. Gastroenterol Res Pract. 2016;2016:6261721.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Gulubova M, Manolova I, Kyurkchiev D, Julianov A, Altunkova I. Decrease in intrahepatic CD56 + lymphocytes in gastric and colorectal cancer patients with liver metastases. APMIS. 2009;117:870–9.PubMedCrossRefGoogle Scholar
  114. 114.
    Marechal R, De Schutter J, Nagy N, Demetter P, Lemmers A, Deviere J, et al. Putative contribution of CD56 positive cells in cetuximab treatment efficacy in first-line metastatic colorectal cancer patients. BMC Cancer. 2010;10:340.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Menon AG, Janssen-van Rhijn CM, Morreau H, Putter H, Tollenaar RA, van de Velde CJ, et al. Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis. Lab Investig J Tech Methods Pathol. 2004;84:493–501.CrossRefGoogle Scholar
  116. 116.
    Sandel MH, Speetjens FM, Menon AG, Albertsson PA, Basse PH, Hokland M, et al. Natural killer cells infiltrating colorectal cancer and MHC class I expression. Mol Immunol. 2005;42:541–6.PubMedCrossRefGoogle Scholar
  117. 117.
    Halama N, Braun M, Kahlert C, Spille A, Quack C, Rahbari N, et al. Natural killer cells are scarce in colorectal carcinoma tissue despite high levels of chemokines and cytokines. Clin Cancer Res. 2011;17:678–89.CrossRefGoogle Scholar
  118. 118.
    Coca S, Perez-Piqueras J, Martinez D, Colmenarejo A, Saez MA, Vallejo C, et al. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer. 1997;79:2320–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Sconocchia G, Eppenberger S, Spagnoli GC, Tornillo L, Droeser R, Caratelli S, et al. NK cells and T cells cooperate during the clinical course of colorectal cancer. Oncoimmunology. 2014;3:e952197.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Furue H, Matsuo K, Kumimoto H, Hiraki A, Suzuki T, Yatabe Y, et al. Decreased risk of colorectal cancer with the high natural killer cell activity NKG2D genotype in Japanese. Carcinogenesis. 2008;29:316–20.CrossRefGoogle Scholar
  121. 121.
    Gharagozloo M, Kalantari H, Rezaei A, Maracy MR, Salehi M, Bahador A, et al. The decrease in NKG2D + Natural Killer cells in peripheral blood of patients with metastatic colorectal cancer. Bratislavske lekarske listy. 2015;116:296–301.PubMedGoogle Scholar
  122. 122.
    Rocca YS, Roberti MP, Arriaga JM, Amat M, Bruno L, Pampena MB, et al. Altered phenotype in peripheral blood and tumor-associated NK cells from colorectal cancer patients. Innate Immun. 2013;19:76–85.PubMedCrossRefGoogle Scholar
  123. 123.
    Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39:782–95.CrossRefGoogle Scholar
  124. 124.
    Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G. Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res. 2011;71:5601–5.PubMedCrossRefGoogle Scholar
  125. 125.
    Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353:2654–66.PubMedCrossRefGoogle Scholar
  126. 126.
    Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene. 2010;29:1093–102.CrossRefGoogle Scholar
  127. 127.
    Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, et al. Tumor-infiltrating FOXP3(+) T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27:186–192.PubMedCrossRefGoogle Scholar
  128. 128.
    Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol. 2010;222:350–66.CrossRefGoogle Scholar
  129. 129.
    Di Caro G, Marchesi F, Laghi L, Grizzi F. Immune cells: plastic players along colorectal cancer progression. J Cell Mol Med. 2013;17:1088–95.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Koch M, Beckhove P, Op den Winkel J, Autenrieth D, Wagner P, Nummer D, et al. Tumor infiltrating T lymphocytes in colorectal cancer: tumor-selective activation and cytotoxic activity in situ. Ann Surg. 2006;244:986–92 (discussion 992–3).CrossRefGoogle Scholar
  131. 131.
    Atreya I, Schimanski CC, Becker C, Wirtz S, Dornhoff H, Schnurer E, et al. The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer. Gut. 2007;56:1572–8.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196:254–65.CrossRefGoogle Scholar
  134. 134.
    Edin S, Wikberg ML, Dahlin AM, Rutegard J, Oberg A, Oldenborg PA, 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:e47045.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Zhou Q, Peng RQ, Wu XJ, Xia Q, Hou JH, Ding Y, et al. The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer. J Transl Med. 2010;8:13.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Kang JC, Chen JS, Lee CH, Chang JJ, Shieh YS. Intratumoral macrophage counts correlate with tumor progression in colorectal cancer. J Surg Oncol. 2010;102:242–8.PubMedCrossRefGoogle Scholar
  137. 137.
    Ohnishi K, Komohara Y, Saito Y, Miyamoto Y, Watanabe M, Baba H, et al. CD169-positive macrophages in regional lymph nodes are associated with a favorable prognosis in patients with colorectal carcinoma. Cancer Sci. 2013;104:1237–44.PubMedCrossRefGoogle Scholar
  138. 138.
    Farinha P, Masoudi H, Skinnider BF, Shumansky K, Spinelli JJ, Gill K, et al. Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood. 2005;106:2169–74.PubMedCrossRefGoogle Scholar
  139. 139.
    Alvaro T, Lejeune M, Camacho FI, Salvado MT, Sanchez L, Garcia JF, et al. The presence of STAT1-positive tumor-associated macrophages and their relation to outcome in patients with follicular lymphoma. Haematologica. 2006;91:1605–12.PubMedGoogle Scholar
  140. 140.
    Taskinen M, Karjalainen-Lindsberg ML, Nyman H, Eerola LM, Leppa S. A high tumor-associated macrophage content predicts favorable outcome in follicular lymphoma patients treated with rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone. Clin Cancer Res. 2007;13:5784–9.PubMedCrossRefGoogle Scholar
  141. 141.
    Kridel R, Xerri L, Gelas-Dore B, Tan K, Feugier P, Vawda A, et al. The prognostic impact of CD163-positive macrophages in follicular lymphoma: a study from the BC cancer agency and the lymphoma study association. Clin Cancer Res. 2015;21:3428–35.PubMedCrossRefGoogle Scholar
  142. 142.
    Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14:399–416.
  143. 143.
    Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F, Szabady RL, et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med. 2013;210:917–31.CrossRefGoogle Scholar
  144. 144.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.CrossRefGoogle Scholar
  145. 145.
    Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56–61.PubMedCrossRefGoogle Scholar
  146. 146.
    Singh PP, Sharma PK, Krishnan G, Lockhart AC. Immune checkpoints and immunotherapy for colorectal cancer. Gastroenterol Rep. 2015;3:289–97.CrossRefGoogle Scholar
  147. 147.
    Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5:43–51.PubMedCrossRefGoogle Scholar
  148. 148.
    Bilgin B, Sendur MA, Bulent Akinci M, Sener Dede D, Yalcin B. Targeting the PD-1 pathway: a new hope for gastrointestinal cancers. Curr Med Res Opin. 2017;33:749–59.PubMedCrossRefGoogle Scholar
  149. 149.
    Passardi A, Canale M, Valgiusti M, Ulivi P. Immune checkpoints as a target for colorectal cancer treatment. Int J Mol Sci. 2017;18:1324.PubMedCentralCrossRefGoogle Scholar
  150. 150.
    Boland PM, Ma WW. Immunotherapy for colorectal cancer. Cancers. 2017;9:50.PubMedCentralCrossRefGoogle Scholar
  151. 151.
    Basso G, Bianchi P, Malesci A, Laghi L. Hereditary or sporadic polyposis syndromes. Best Pract Res Clin Gastroenterol. 2017;31:409–17.PubMedCrossRefGoogle Scholar
  152. 152.
    Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22:813–20.CrossRefGoogle Scholar
  153. 153.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182–91.PubMedCrossRefGoogle Scholar
  155. 155.
    Khosravi Shahi P, Fernandez Pineda I. Tumoral angiogenesis: review of the literature. Cancer Investig. 2008;26:104–8.CrossRefGoogle Scholar
  156. 156.
    Achen MG, Stacker SA. Molecular control of lymphatic metastasis. Ann N Y Acad Sci. 2008;1131:225–34.CrossRefGoogle Scholar
  157. 157.
    Bonecchi R, Galliera E, Borroni EM, Corsi MM, Locati M, Mantovani A. Chemokines and chemokine receptors: an overview. Front Biosci. 2009;14:540–51.Google Scholar
  158. 158.
    Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121–7.PubMedCrossRefGoogle Scholar
  159. 159.
    Murphy PM. The molecular biology of leukocyte chemoattractant receptors. Annu Rev Immunol. 1994;12:593–633.PubMedCrossRefGoogle Scholar
  160. 160.
    Scotton C, Milliken D, Wilson J, Raju S, Balkwill F. Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours. Br J Cancer. 2001;85:891–7.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Conti I, Rollins BJ. CCL2 (monocyte chemoattractant protein-1) and cancer. Semin Cancer Biol. 2004;14:149–54.CrossRefGoogle Scholar
  162. 162.
    Balkwill F, Coussens LM. Cancer: an inflammatory link. Nature. 2004;431:405–6.PubMedCrossRefGoogle Scholar
  163. 163.
    Kulbe H, Levinson NR, Balkwill F, Wilson JL. The chemokine network in cancer—much more than directing cell movement. Int J Dev Biol. 2004;48:489–96.PubMedCrossRefGoogle Scholar
  164. 164.
    Trujillo G, O’Connor EC, Kunkel SL, Hogaboam CM. A novel mechanism for CCR4 in the regulation of macrophage activation in bleomycin-induced pulmonary fibrosis. Am J Pathol 2008;172:1209–21.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Mantovani A, Bussolino F, Introna M. Cytokine regulation of endothelial cell function: from molecular level to the bedside. Immunol Today. 1997;18:231–40.CrossRefGoogle Scholar
  166. 166.
    Sickert D, Aust DE, Langer S, Haupt I, Baretton GB, Dieter P. Characterization of macrophage subpopulations in colon cancer using tissue microarrays. Histopathology. 2005;46:515–21.CrossRefGoogle Scholar
  167. 167.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–6.CrossRefGoogle Scholar
  168. 168.
    Kawada K, Hosogi H, Sonoshita M, Sakashita H, Manabe T, Shimahara Y, et al. Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes. Oncogene. 2007;26:4679–88.PubMedCrossRefGoogle Scholar
  169. 169.
    Lin K, Zou R, Lin F, Zheng S, Shen X, Xue X. Expression and effect of CXCL14 in colorectal carcinoma. Mol Med Rep. 2014;10:1561–8.PubMedCrossRefGoogle Scholar
  170. 170.
    Akeus P, Langenes V, von Mentzer A, Yrlid U, Sjoling A, Saksena P, et al. Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC(Min/+) mice. Cancer Immunol Immun. 2014;63:807–19.CrossRefGoogle Scholar
  171. 171.
    Dimberg J, Skarstedt M, Lofgren S, Zar N, Matussek A. Protein expression and gene polymorphism of CXCL10 in patients with colorectal cancer. Biomed Rep. 2014;2:340–3.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Lu J, Zhao J, Feng H, Wang P, Zhang Z, Zong Y, et al. Antitumor efficacy of CC motif chemokine ligand 19 in colorectal cancer. Digest Dis Sci. 2014;59:2153–62.PubMedCrossRefGoogle Scholar
  173. 173.
    Cheng XS, Li YF, Tan J, Sun B, Xiao YC, Fang XB, et al. CCL20 and CXCL8 synergize to promote progression and poor survival outcome in patients with colorectal cancer by collaborative induction of the epithelial-mesenchymal transition. Cancer Lett. 2014;348:77–87.PubMedCrossRefGoogle Scholar
  174. 174.
    Yamada S, Shimada M, Utsunomiya T, Morine Y, Imura S, Ikemoto T, et al. CXC receptor 4 and stromal cell-derived factor 1 in primary tumors and liver metastases of colorectal cancer. J Surg Res. 2014;187:107–12.Google Scholar
  175. 175.
    Heckmann D, Maier P, Laufs S, Li L, Sleeman JP, Trunk MJ, et al. The disparate twins: a comparative study of CXCR4 and CXCR7 in SDF-1alpha-induced gene expression, invasion and chemosensitivity of colon cancer. Clin Cancer Res. 2014;20:604–16.CrossRefGoogle Scholar
  176. 176.
    D’Alterio C, Avallone A, Tatangelo F, Delrio P, Pecori B, Cella L, et al. A prognostic model comprising pT stage, N status, and the chemokine receptors CXCR4 and CXCR7 powerfully predicts outcome in neoadjuvant resistant rectal cancer patients. Int J Cancer Journal international du cancer. 2014;135:379–90.Google Scholar
  177. 177.
    Cao B, Yang Y, Pan Y, Jia Y, Brock MV, Herman JG, et al. Epigenetic silencing of CXCL14 induced colorectal cancer migration and invasion. Discovery medicine. 2013;16:137–47.Google Scholar
  178. 178.
    Zeng J, Yang XD, Cheng L, Liu R, Lei YL, Dong DD, et al. Chemokine CXCL14 is associated with prognosis in patients with colorectal carcinoma after curative resection. J Transl Med. 2013;11:6.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Tada N, Tsuno NH, Kawai K, Murono K, Nirei T, Ishihara S, et al. Changes in the plasma levels of cytokines/chemokines for predicting the response to chemoradiation therapy in rectal cancer patients. Oncol Rep. 2014;31:463–71.CrossRefGoogle Scholar
  180. 180.
    Malara A, Currao M, Gruppi C, Celesti G, Viarengo G, Buracchi C, et al. Megakaryocytes contribute to the bone marrow-matrix environment by expressing fibronectin, type IV collagen, and laminin. Stem Cells. 2014;32:926–37.CrossRefGoogle Scholar
  181. 181.
    West NR, McCuaig S, Franchini F, Powrie F. Emerging cytokine networks in colorectal cancer. Nat Rev Immunol. 2015;15:615–29.CrossRefGoogle Scholar
  182. 182.
    Olsen RS, Nijm J, Andersson RE, Dimberg J, Wagsater D. Circulating inflammatory factors associated with worse long-term prognosis in colorectal cancer. WJG. 2017;23:6212–9.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Chang PH, Pan YP, Fan CW, Tseng WK, Huang JS, Wu TH, et al. Pretreatment serum interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha levels predict the progression of colorectal cancer. Cancer Med. 2016;5:426–33.CrossRefGoogle Scholar
  184. 184.
    Ray AL, Berggren KL, Restrepo Cruz S, Gan GN, Beswick EJ. Inhibition of MK2 suppresses IL-1beta, IL-6, and TNF-alpha-dependent colorectal cancer growth. Int J Cancer. 2017.
  185. 185.
    Wu J, Wang Y, Xu X, Cao H, Sahengbieke S, Sheng H, et al. Transcriptional activation of FN1 and IL11 by HMGA2 promotes the malignant behavior of colorectal cancer. Carcinogenesis. 2016;37:511–21.Google Scholar
  186. 186.
    Merlano MC, Granetto C, Fea E, Ricci V, Garrone O. Heterogeneity of colon cancer: from bench to bedside. ESMO Open. 2017;2:e000218.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Housseau F, Wu S, Wick EC, Fan H, Wu X, Llosa NJ, et al. Redundant innate and adaptive sources of IL17 production drive colon tumorigenesis. Cancer Res. 2016;76:2115–24.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 2009;9:480–90.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Fabio Grizzi
    • 1
  • Gianluca Basso
    • 2
  • Elena Monica Borroni
    • 5
  • Tommaso Cavalleri
    • 2
  • Paolo Bianchi
    • 2
  • Sanja Stifter
    • 6
  • Maurizio Chiriva-Internati
    • 7
  • Alberto Malesci
    • 2
    • 3
    • 5
  • Luigi Laghi
    • 2
    • 3
    • 4
  1. 1.Department of Immunology and InflammationHumanitas Clinical and Research CenterRozzanoItaly
  2. 2.Laboratory of Molecular GastroenterologyHumanitas Clinical and Research CenterRozzanoItaly
  3. 3.Department of GastroenterologyHumanitas Clinical and Research CenterRozzanoItaly
  4. 4.Hereditary Cancer Genetics ClinicHumanitas Clinical and Research CenterRozzanoItaly
  5. 5.Department of Biotechnology and Translational MedicineUniversity of MilanMilanItaly
  6. 6.Department of Pathology, School of MedicineUniversity of RijekaRijekaCroatia
  7. 7.Department of Lymphoma and MyelomaThe University of Texas MD Anderson Cancer CenterHoustonUSA

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