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Cited by 434Cancer Immunotherapy and BiomarkersColorectal Cancer Treatments and StudiesColorectal Cancer Surgical Treatments

Unique Ectopic Lymph Node-Like Structures Present in Human Primary Colorectal Carcinoma Are Identified by Immune Gene Array Profiling

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Coppola, Domenico, Nebozhyn, Michael, Khalil, Farah, Dai, Hongyue, Yeatman, Timothy, Loboda, Andrey, Mulé, James J.·2011·The American Journal of Pathology
DOI 10.1016/j.ajpath.2011.03.007PMC PMC3123872
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Abstract

We hypothesized that immune gene-related signatures would predict the presence of unique histological features of lymphoid cell infiltrates in colorectal carcinoma (CRC) that correlate with clinical parameters. Metagene analysis with gene chip technology was performed on 326 CRCs, which were then sorted by low versus high gene scores. Microscopically, CRCs with a high gene score revealed a marked host immune response organized, remarkably, as lymphoid follicles. Proliferation involved both B and T cells. In every case, the presence of CD79a(+) B-cell precursors was identified, suggesting that the lymphoid follicles represent newly formed, ectopic lymph node-like structures. CD21(+) dendritic cells were present within the follicular germinal centers, and CD3(+) T cells were localized mainly in the parafollicular cortex zone surrounding the B-cell area of the follicles. A strong correlation between a 12-chemokine gene subset of the molecular profile and the presence of ectopic lymph node-like structures was associated with better patient survival independent of tumor staging, site location, microsatellite instability or stability, and patient treatment. These findings suggest beneficial, intratumoral immune cell priming and raise the possibility of immunotherapy intervention decisions based on molecular signatures that can identify the presence of tumor-localized, ectopic lymph node-like structures.

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  • CXCL10 expression has been correlated with the presence of tumor-associated tertiary lymphoid structures.

    “Also, as a member of the 12-chemokine gene signature classifier33, its expression has been correlated with the presence of tumor-associated tertiary lymphoid structures50–52 which are rapidly emerging as a powerful prognostic marker in melanoma and a number of other cancer types53–55.”

    From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [50]

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Research works printed but not linked: 46

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer Statistics. CA Cancer J Clin 2008, 58:71-96
  2. Coronella JA, Spier C, Welch M, Trevor KT, Stopeck AT, Villar H, Hersh EM: Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. J Immunol 2002, 169:1829 -1836
  3. Coronella-Wood JA, Hersh EM: Naturally occurring B-cell responses to breast cancer. Cancer Immunol Immunother 2003, 52:715-738
  4. Bell D, Chomarat P, Broyles D, Netto G, Harb GM, Lebecque S, Valladeau J, Davoust J, Palucka KA, Banchereau J: In breast carci- noma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 1999, 190:1417-1426
  5. Aspord C, Pedroza-Gonzalez A, Gallegos M, Tindle S, Burton EC, Su D, Marches F, Banchereau J, Palucka AK: Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4ϩ T cells that facilitate tumor development. J Exp Med 2007, 204:1037-1047
  6. Kurabayashi A, Furihata M, Matsumoto M, Hayashi H, Ohtsuki Y: Distribution of tumor-infiltrating dendritic cells in human non-small cell lung carcinoma in relation to apoptosis. Pathol Int 2004, 54:302-310
  7. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, Lebecque S, Fridman WH, Cadranel J: Long-term survival for patients with non- small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 2008, 26:4410 -4417
  8. Eisenthal A, Polyvkin N, Bramante-Schreiber L, Misonznik F, Hassner A, Lifschitz-Mercer B: Expression of dendritic cells in ovarian tumors correlates with clinical outcome in patients with ovarian cancer. Hum Pathol 2001, 32:803-807
  9. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evde- mon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004, 10:942-949
  10. Singh P, Coskun ZZ, Goode C, Dean A, Thompson-Snipes L, Dar- lington G: Lymphoid neogenesis and immune infiltration in aged liver. Hepatology 2008, 47:1680 -1690
  11. Carragher DM, Rangel-Moreno J, Randall TD: Ectopic lymphoid tis- sues and local immunity. Semin Immunol 2008, 20:26 -42
  12. Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, Ohuchi A, Ohuchi K, Shiiba K, Kurokawa Y, Satomi S: Intraepithelial CD8ϩ T-cell-count becomes a prognostic factor after a longer follow up period in human colorectal carcinoma: possible association with sup- pression of micrometastasis. Br J Cancer 2004, 91:1711-1717
  13. Nagorsen D, Keilholz U, Rivoltini L, Schmittel A, Letsch A, Asemissen AM, Berger G, Buhr HJ, Thiel E, 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 2000, 60:4850 -4854
  14. Watanabe T, Kobunai T, Toda E, Yamamoto Y, Kanazawa T, Kazama Y, Tanaka J, Tanaka T, Konishi T, Okayama Y, Sugimoto Y, Oka T, Sasaki S, Muto T, Nagawa H: Distal colorectal cancers with micro- satellite instability (MSI) display distinct gene expression profiles that are different from proximal MSI cancers. Cancer Res 2006, 66:9804 - 9808
  15. Giacomini CP, Leung SY, Chen X, Yuen ST, Kim YH, Bair E, Pollack JR: A gene expression signature of genetic instability in colon cancer. Cancer Res 2005, 65:9200 -9205
  16. Kruhøffer M, Jensen JL, Laiho P, Dyrskjøt L, Salovaara R, Arango D, Birkenkamp-Demtroder K, Sørensen FB, Christensen LL, Buhl L, Mecklin JP, Järvinen H, Thykjaer T, Wikman FP, Bech-Knudsen F, Juhola M, Nupponen NN, Laurberg S, Andersen CL, Aaltonen LA, Ørntoft TF: Gene expression signatures for colorectal cancer micro- satellite status and HNPCC. Br J Cancer 2005, 92:2240 -2248
  17. Loboda A, Nebozhyn MV, Watters JW, Buser CA, Shaw PM, Huang PS, Van't Veer L, Tollenaar RA, Jackson DB, Agrawal D, Dai H, Yeatman TJ: EMT is the dominant program in human colon cancer. BMC Med Genomics 2011, 4:9 44
  18. Coppola et al AJP July 2011, Vol. 179, No. 1
  19. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Veli-Matti K: Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorec- tal cancer. J Pathol 1997, 182:318 -324
  20. Chaves P, Cruz C, Lage P, Claro I, Cravo M, Leitao CN, Soares J: Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype [Erratum appeared in J Pathol 2001;193:279]. J Pathol 2000, 191:355-360
  21. Kakar S, Aksoy S, Burgart LJ, Smyrk TC: Muscinous carcinoma of the colon: correlation of loss of mismatch repair enzymes with clinico- pathologic features and survival. Mod Pathol 2004, 17:696 -700
  22. Tougeron D, Fauquembergue E, Rouquette A, Le Pessot F, Sesboüé R, Laurent M, Berthet P, Mauillon J, Di Fiore F, Sabourin JC, Michel P, Tosi M, Frébourg T, Latouche JB: Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations. Mod Pathol 2009, 22:1186 -1195
  23. Luscieti P, Hubschmid T, Cottier H, Hess MW, Sobin LH: Human lymph node morphology as a function of age and site. J Clin Pathol 1980, 33:454 -461
  24. Zeid NA, Muller HK: S100 positive dendritic cells in human lung tumors associated with cell differentiation and enhanced survival. Pathology 1993, 25:338 -343
  25. Nagorsen D, Voigt S, Berg E, Stein H, Thiel E, Loddenkemper C: Tumor-infiltrating macrophages and dendritic cells in human colorec- tal cancer: relation to local regulatory T cells, systemic T-cell re- sponse against tumor-associated antigens and survival. J Transl Med 2007, 5:62
  26. Michael-Robinson JM, Biemer-Hüttmann A, Purdie DM, Walsh MD, Simms LA, Biden KG, Young JP, Leggett BA, Jass JR, Radford-Smith GL: Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status. Gut 2001, 48:360 -366
  27. Coppola D, Mulé JJ: Ectopic lymph nodes within human solid tumors. J Clin Oncol 2008, 26:4369 -4370
  28. Timmer TC, Baltus B, Vondenhoff M, Huizinga TW, Tak PP, Verweij CL, Mebius RE, van der Pouw Kraan TC: Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: identification of the interleukin-7 signaling pathway in tissues with lymphoid neogenesis. Arthritis Rheum 2007, 56:2492-2502
  29. Olszewski WL: De novo lymph node formation in chronic inflammation of the human leg. Ann N Y Acad Sci 2002, 979:166 -177
  30. Marinkovic T, Garin A, Yokota Y, Fu YX, Ruddle NH, Furtado GC, Lira SA: Interaction of mature CD3ϩCD4ϩ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid. J Clin Invest 2006, 116:2622-2632
  31. Kim MY, Gaspal FM, Wiggett HE, McConnell FM, Gulbranson-Judge A, Raykundalia C, Walker LS, Goodall MD, Lane PJ: CD4ϩCD3Ϫ accessory cells costimulate primed CD4 T cells through OX40 and CD30 at sites where T cells collaborate with B cells. Immunity 2003, 18:643-654
  32. van de Pavert SA, Olivier BJ, Goverse G, Vondenhoff MF, Greuter M, Beke P, Kusser K, Höpken UE, Lipp M, Niederreither K, Blomhoff R, Sitnik K, Agace WW, Randall TD, de Jonge WJ, Mebius RE: Chemo- kine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat Immunol 2009, 10:1193- 1199
  33. Kirk CJ, Hartigan-O'Connor D, Mulé JJ: The dynamics of the T-cell antitumor response: chemokine-secreting dendritic cells can prime tumor-reactive T cells extranodally. Cancer Res 2001, 61:8794 -8802
  34. Dubinett SM, Lee JM, Sharma S, Mulé JJ: Chemokines: can effector cells be re-directed to the site of tumor? Cancer J 2010, 167:325-335
  35. Hoelzinger DB, Smith SE, Mirza N, Dominguez AL, Manrique SZ, Lustgarten J: Blockade of CCL1 inhibits T regulatory cell suppressive function enhancing tumor immunity without affecting T effector re- sponses. J Immunol 2010, 184:6833-6842
  36. Mira E, León B, Barber DF, Jiménez-Baranda S, Goya I, Almonacid L, Márquez G, Zaballos A, Martínez-A C, Stein JV, Ardavín C, Mañes S: Statins induce regulatory T cell recruitment via a CCL1 dependent pathway. J Immunol 2008, 181:3524 -3534
  37. Yamazaki T, Yang XO, Chung Y, Fukunaga A, Nurieva R, Pappu B, Martin-Orozco N, Kang HS, Ma L, Panopoulos AD, Craig S, Watowich SS, Jetten AM, Tian Q, Dong C: CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol 2008, 181:8391-8401
  38. Toulza F, Nosaka K, Tanaka Y, Schioppa T, Balkwill F, Taylor GP, Bangham CR: Human T-lymphotropic virus type 1-induced CC chemokine ligand 22 maintains a high frequency of functional FoxP3ϩ regulatory T cells. J Immunol 2010, 185:183-189
  39. Manzo A, Paoletti S, Carulli M, Blades MC, Barone F, Yanni G, Fitzgerald O, Bresnihan B, Caporali R, Montecucco C, Uguccioni M, Pitzalis C: Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur J Immunol 2005, 35:1347-1359
  40. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lago- rce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006, 313:1960 -1964
  41. Bogunovic D, O'Neill DW, Belitskaya-Levy I, Vacic V, Yu YL, Adams S, Darvishian F, Berman R, Shapiro R, Pavlick AC, Lonardi S, Zavadil J, Osman I, Bhardwaj N: Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient sur- vival. Proc Natl Acad Sci USA 2009, 106:20429 -20434
  42. Geurts van Kessel CH, Willart MA, Bergen IM, van Rijt LS, Muskens F, Elewaut D, Osterhaus AD, Hendriks R, Rimmelzwaan GF, Lambrecht BN: Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J Exp Med 2009, 206:2339 -2349
  43. Tsunoda T, Yamakawa M, Takahashi T: Differential expression of Ca(2ϩ)-binding proteins on follicular dendritic cells in non-neoplastic and neoplastic lymphoid follicles. Am J Pathol 1999, 155:805-814
  44. Charo IF, Ransohoff RM: The many roles of chemokines and chemo- kine receptors in inflammation. N Engl J Med 2006, 354:610 -621
  45. Rosenberg SA, Dudley ME: Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 2009, 21:233- 240
  46. Yeatman T, Mulé JJ, Dalton WS, Sullivan D: On the eve of personal- ized medicine in oncology. Cancer Res 2008, 68:7250 -7252

Cited by

Sorted by citations

Authors
Coppola, D., Nebozhyn, M., Khalil, F., Dai, H., Yeatman, T., Loboda, A., & Mulé, J. J.
Affiliations
  • Moffitt Cancer Center (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author
Mulé, James J.
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2011-07
Volume
179
Issue
1
Pages
37-45
ISSN
0002-9440 (ISSN-L)
DOI
10.1016/j.ajpath.2011.03.007
PMC
PMC3123872
OpenAlex
W2112382960
Cited by
434
References
2
Citations by year
2026: 41 · 2025: 50 · 2024: 59 · 2023: 54 · 2022: 42 · 2021: 34 · 2020: 26 · 2019: 14 · 2018: 30 · 2017: 17 · 2016: 14 · 2015: 16 · 2014: 16 · 2013: 12 · 2012: 6
FWCI
5.52
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
Keywords
colorectal cancer, lymphoid follicles, germinal center, T cells, chemokine genes, antitumor immunity, patient survival, immunotherapy
MeSH terms
Adenocarcinoma, Aged, Aged, 80 and over, B-Lymphocytes, Dendritic Cells, Female, Humans, Immunoenzyme Techniques, Liver, Liver Neoplasms, Lymph Nodes, Male, Middle Aged, Neoplasm Staging, Prognosis, RNA, Messenger, T-Lymphocytes, Biomarkers, Tumor, Colorectal Neoplasms, Survival Rate, Germinal Center, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, CD79 Antigens, Microsatellite Instability

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