Immune structures of the greater omentum and their role in cancer metastasis

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Abstract

Omental malignant metastases are one of the challenging issues in oncology. The article provides a review of recent studies on the structure and functions of immune compartments of the greater omentum and their characteristic features that promote or inhibit tumor dissemination. The cellular composition of lymphoid nodules and milky spots is described, and functional and phenotypic properties of macrophages and lymphocytes are shown. Unique subpopulations of immunocompetent cells typical of this particular organ, as well as produced cytokines, are characterized. Particular attention is paid to the visceral adipose tissue surrounding immunocompetent cells and its effect on their functions. Analysis of the literature data has revealed a dual role, i.e. both protective and immunosuppressive one, of lymphoid structures of the greater omentum. The former is apparently associated mainly with a response to bacterial pathogens, while the latter is realized in cancer metastasis. The article focuses on immunological mechanisms that create local conditions for the growth and development of metastases, in particular, proinflammatory cytokines, chemokines, growth factors secreted by immune, tumor and mesothelial cells, and on the importance of the surrounding visceral adipose tissue for this process. The multidirectional prognostic significance of some local cellular and cytokine factors in cancer metastasis to the omentum and peritoneum is demonstrated. Possible approaches to treatment involving immunotherapy should be aimed at both elimination of tumor cells and overcoming the immunosuppressive environment. In this regard, reprogramming of macrophages, correction of hypoxic microenvironment, and the search for new control points seem promising.

About the authors

E Yu Zlatnik

Rostov Research Institute of Oncology

Email: iftrnioi@yandex.ru
SPIN-code: 4137-7410
Russian Federation, Rostov-on-Don, Russia

E M Nepomnyashchaya

Rostov Research Institute of Oncology

Author for correspondence.
Email: iftrnioi@yandex.ru
SPIN-code: 8930-9580
Russian Federation, Rostov-on-Don, Russia

O E Zhenilo

Rostov Research Institute of Oncology

Email: iftrnioi@yandex.ru
SPIN-code: 4078-7080
Russian Federation, Rostov-on-Don, Russia

V P Nikitina

Rostov Research Institute of Oncology

Email: iftrnioi@yandex.ru
SPIN-code: 4716-7390
Russian Federation, Rostov-on-Don, Russia

E V Verenikina

Rostov Research Institute of Oncology

Email: iftrnioi@yandex.ru
SPIN-code: 6610-7824
Russian Federation, Rostov-on-Don, Russia

I S Nikitin

Rostov Research Institute of Oncology

Email: iftrnioi@yandex.ru
SPIN-code: 2005-5880
Russian Federation, Rostov-on-Don, Russia

References

  1. Kit O.I., Shaposhnikov A.V., Zlatnik E.Yu. et al. Local cellular immunity in adenocarcinoma and polyps. Sibirskoe meditsinskoe obozrenie. 2012; (4): 11–16. (In Russ.)
  2. Clark R., Krishnan V., Schoof M. et al. Milky spots promote ovarian cancer metastatic colonization of peritoneal adipose in experimental models. Am. J. Pathol. 2013; 183: 576–591. doi: 10.1016/j.ajpath.2013.04.023.
  3. Gerber S.A., Rybalko V.Y., Bigelow C.E. et al. Prefe­rential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am. J. Pathol. 2006; 169: 1739–1752. doi: 10.2353/ajpath.2006.051222.
  4. Karasyova O.V., Roshalʹ L.M., Nekrutov A.V. Greater omentum: morphofunctional characteristics and clinical significance in pediatrics. Voprosy sovremennoy pediatrii. 2007; 6 (6): 58–63. (In Russ.)
  5. Liu J., Geng X., Li Y. Milky spots: omental functio­nal units and hotbeds for peritoneal cancer metastasis. Tumor Boil. 2016; 37: 5715–5726. doi: 10.1007/s13277-016-4887-3.
  6. Murray P.J., Wynn T.A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 2011; 11 (11): 723–737. doi: 10.1038/nri3073.
  7. Okabe Y., Medzhitov R. Tissue-specific signals control reversible program of localization and functional pola­rization of macrophages. Cell. 2014; 157 (4): 832–844. doi: 10.1016/j.cell.2014.04.016.
  8. Cherdyntseva N.V., Mitrofanova I.V., Buldakov M.A. et al. Macrophages and tumor progression: on the way to macrophage-specific therapy. Byulletenʹ sibirskoy meditsiny. 2017; 16 (4): 61–74. (In Russ.)
  9. Sainz J.B., Martin B., Tatari M. et al. ISG15 is a cri­tical microenvironmental factor for pancreatic cancer stem cells. Cancer Res. 2014; 74 (24): 7309–7320. doi: 10.1158/0008-5472.CAN-14-1354.
  10. Cohen C.A., Shea A.A., Heffron C.L. et al. Intra-­abdominal fat depots represent distinct immunomodulatory microenvironments: a murine model. PLoS One. 2013; 8 (6): e66477. doi: 10.1371/journal.pone.0066477.
  11. Rangel-Moreno J., Moyron-Quiroz J.E., Carra­gher D.M. et al. Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity. 2009; 30 (5): 731–743. doi: 10.1016/j.immuni.2009.03.014.
  12. Yarilin A.A. Immunologiya. Uchebnik. (Immunology. Textbook.) Moscow: ­GEOTAR-Media. 2010; 752 p. (In Russ.)
  13. Zhang Ch., Xin H., Zhang W. et al. CD5 binds to interleukin-6 and induces a feed-forward loop with the transcription factor STAT3 in B cells to promote cancer. Immunity. 2016; 44: 913–923. doi: 10.1016/j.immuni.2016.04.003.
  14. Chulkova S.V., Sholokhova E.N., Grishchenko N.V. et al. The role of B-1 lymphocytes in antitumor immunity in patients with gastric cancer. Rossiyskiy bioterapevticheskiy zhurnal. 2018; 17 (4): 64–70. (In Russ.)
  15. McMurchy A.N., Bushell A., Levings M.K. et al. Moving to tolerance: clinical application of T regulatory cells. Semin. Immunol. 2011; 23 (4): 304–313. doi: 10.1016/j.smim.2011.04.001.
  16. Zlatnik E.Yu., Novikova I.A., Nepomnyashchaya E.M. et al. Possibility of predicting the efficiency of soft tissue sarcoma treatment on the basis of features of their immunological ­microenvironment. Kazanskiy meditsinskiy zhurnal. 2018; 99 (1): 167–173. (In Russ.)
  17. Spits H., Artis D., Colonna M. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nat. Rev. Immunol. 2013; 13: 145–149. doi: 10.1038/nri3365.
  18. Jackson-Jones L.H., Duncan S.M., Magalhaes M.S. et al. Fat-associated lymphoid clusters control local IgM secretion during pleural infection and lung inflamemation. Nat. Commun. 2016; 7: 12 651. doi: 10.1038/ncomms12651.
  19. Jones D.D., Racine R., Wittmer S.T. et al. The omentum is a site of protective IgM production during intracellular bacterial infection. Infect. Immun. 2015; 83 (5): 2139–2147. doi: 10.1128/IAI.00295-15.
  20. Lu B., Yang M., Wang Q. Interleukin-33 in tumorigenesis, tumor immune evasion, and cancer immunotherapy. J. Mol. Med. 2016; 94: 535–543. doi: 10.1007/s00109-016-1397-0.
  21. Fessler J., Matson V., Gajewski T.F. Exploring the emerging role of themicrobiome in cancer immunotherapy. J. Immun. Ther. Cancer. 2019; 7: 108–123. doi: 10.1186/s40425-019-0574-4.
  22. Cipolletta D., Cohen P., Spiegelman B.M. et al. Appearance and disappearance of the mRNA signature cha­racteristic of Treg cells in visceral adipose tissue: age, diet, and PPARɣ effects. Proc. Natl. Acad. Sci. USA. 2015; 112 (2): 482–487. doi: 10.1073/pnas.1423486112.
  23. Vasanthakumar A., Moro K., Xin A. et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat. Immunol. 2015; 16 (3): 276–285. doi: 10.1038/ni.3085.
  24. Bapat S.P., Myoung S.J., Fang S. et al. Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature. 2015; 528 (7580): 137–141. doi: 10.1038/nature16151.
  25. Horikawa N., Abiko K., Matsumura N. et al. Expression of vascular endothelial growth factor in ova­rian cancer inhibits tumor immunity through the accumulation of myeloid-derived suppressor cells. Clin. Cancer Res. 2017; 23 (2): 587–599. doi: 10.1158/1078-0432.CCR-16-0387.
  26. Obermajer N., Wong J.L., Edwards R.P. et al. Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. J. Exp. Med. 2013; 210 (7): 1433–1445. doi: 10.1084/jem.20121277.
  27. Meza-Perez S., Randall T.D. Immunological functions of the omentum. Trends Immunol. 2017; 38 (7): 526–536. doi: 10.1016/j.it.2017.03.002.
  28. Stadlmann S., Raffeiner R., Amberger A. et al. Disruption of the integrity of human peritoneal mesothelium by interleukin-1beta and tumor necrosis factor- alpha. Virchows Arch. 2003; 443: 678–685. doi: 10.1007/s00428-003-0867-2.
  29. Lewis J.S., Landers R.J., Underwood J.C. et al. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J. Pathol. 2000; 192: 150–158. doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH687>3.0.CO;2-G.
  30. Burke B., Giannoudis A., Corke K.P. et al. Hypo­xia-induced gene expression in human macrophages: implications for ischemic tis- sues and hypoxia-regulated gene therapy. Am. J. Pathol. 2003; 163: 1233–1243. doi: 10.1016/S0002-9440(10)63483-9.
  31. Miao Z.F., Wang Z.N., Zhao T.T. et al. Peritoneal milky spots serve as a hypoxic niche and favor gastric cancer stem/progenitor cell peritoneal dissemination through hypoxia-inducible factor 1α. Stem. Cells. 2014; 32: 3062–3074. doi: 10.1002/stem.1816.
  32. Cao L., Hu X., Zhang Y. et al. Omental milky spots in screening gastric cancer stem cells. Neoplasma. 2011; 58: 20–26. doi: 10.4149/neo_2011_01_20.
  33. Cao L., Hu X., Zhang J. et al. The role of the CCL22-CCR4 axis in the metastasis of gastric cancer cells into omental milky spots. J. Transl. Med. 2014; 12: 267. doi: 10.1186/s12967-014-0267-1.
  34. Mnikhovich M.V., Vernigorodskiy S.V., Bunʹkov K.V. et al. Epithelial-mesenchimal transition transdifferentiation, reprogramming and metaplasia: modern view on the problem. Vestnik Natsionalʹnogo mediko-khirurgicheskogo Tsentra im. N.I. Pirogova. 2018; 13 (2): 145–152. (In Russ.)
  35. Sorensen E.W., Gerber S.A., Sedlacek A.L. et al. Omental immune aggregates and tumor metastasis within the peritoneal cavity. Immunol. Res. 2009; 45 (2–3): 185–194. doi: 10.1007/s12026-009-8100-2.
  36. Sato E., Olson S.H., Ahn J. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cells ratio are associated with favorable prognosis in ovarian cancer. PNAS. 2005; 102 (51): 18 538–18 543. doi: 10.1073/pnas.0509182102.
  37. Zueva E.V., Niko­gosyan S.O., Kuznetsov V.V. et al. Immunohistroche­mistry and flow cytometric characteristics of intratumoral lymphocytes in ovarian serous adenocarcinoma. Opukholi zhenskoy reproduktivnoy sistemy. 2009; (3–4): 117–121. (In Russ.)
  38. Nishimura S., Manabe I., Nagasaki M. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 2009; 15; 914–920. doi: 10.1038/nm.1964.
  39. Berezhnaya N.M., Chekhun V.F. Immunologiya zlo­kachestvennogo rosta. (Immunology of malignant growth.) Kiev: Naukova dumka. 2005; 792 p. (In Russ.)
  40. Nieman K.M., Kenny H.A., Penicka C.V. et al. Adi­pocytes promote ovarian cancer metastasis and provide ener­gy for rapid tumor growth. Nat. Med. 2011; 17: 1498–1503. doi: 10.1038/nm.2492.
  41. Schaible U.E., Kaufmann H.E. CD1 molecules and CD1-dependent T cells in bacterial infections: a link from innate to acquired immunity. Semin. Immunol. 2000; 12-6: 527–535. doi: 10.1006/smim.2000.0272.
  42. Sag D., Krause P., Hedrick C.C. et al. IL-10-produ­cing NKT10 cells are a distinct regulatory invariant NKT cell subset. J. Clin. Invest. 2014; 124 (9): 3725–3740. doi: 10.1172/JCI72308.
  43. Shah S., Lowery E., Braun R.K. et al. Cellular basis of tissue regeneration by omentum. PLoS ONE. 2012; 7 (6): e38368. doi: 10.1371/journal.pone.0038368.
  44. Han S.J., Glatman Z.A., Andrade-Oliveira V. et al. White adipose tissue is a reservoir for memory T cells and promotes protective memory responses to infection. ­Immunity. 2017; 47: 1154–1168.e6. doi: 10.1016/j.immuni.2017.11.009.
  45. Conroy M.J., Maher S.G., Melo A.M. et al. Identifying a novel role for Fractalkine (CX3CL1) in memory CD8+ T cell accumulation in the omentum of obesity-associated cancer patients. Front. Immunol. 2018; 9: 1867. doi: 10.3389/fimmu.2018.01867.
  46. Shah R., Hinkle C.C., Ferguson J.F. et al. Fractalkine is a novel human adipochemokine associated with type 2 diabetes. Diabetes. 2011; 60: 1512–1518. doi: 10.2337/db10-0956.
  47. Conroy M.J., Fitzgerald V., Doyle S.L. et al. The microenvironment of visceral adipose tissue and liver alter na­tural killer cell viability and function. J. Leukoc. Biol. 2016; 100 (6): 1435–1442. doi: 10.1189/jlb.5AB1115-493RR.
  48. Zhang X.L., Yang Y.S., Xu D.P. et al. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J. Surg. 2009; 33 (10): 2112–2118. doi: 10.1007/s00268-009-0142-z.
  49. Shan T., Liu W., Kuang S. Fatty acid binding protein 4 expression marks a population of adipocyte proge­nitors in white and brown adipose tissues. FASEB J. 2013; 27 (1): 277–287. doi: 10.1096/fj.12-211516.
  50. Wouters M.C., Komdeur F.L., Workel H.H. et al. Treatment regimen, surgical outcome, and T-cell differentiation influence prognostic benefit of tumor-infiltrating lymphocytes in high-grade serous ovarian cancer. Clin. Cancer Res. 2016; 22 (3): 714–724. doi: 10.1158/1078-0432.CCR-15-1617.
  51. Curiel T.J., Coukos G., Zou L. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 2004; 10 (9): 942–949. doi: 10.1038/nm1093.
  52. Zlatnik E.Yu., Goroshinskaya I.A., Ushakova N.D. et al. Immunologic and biochemical humo­ral factors of ascitic fluid of patients with ovarian cancer and its components obtained by means of filtrating detoxication. Zhurnal RUDN, seriya “Meditsina”. 2008; (8): 614–618.
  53. Ikehara Y., Shiuchi N., Kabata-Ikeharaet S. al. Effective induction of anti-tumor immune responses with oligomannose-coated liposome targeting to intraperito­neal phagocytic cells. Cancer Lett. 2008; 260 (1–2): 137–145. doi: 10.1016/j.canlet.2007.10.038.
  54. Casazza A., Laoui D., Wenes M. et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell. 2013; 24: 695–709. doi: 10.1016/j.ccr.2013.11.007.
  55. Brown D., Trowsdale J., Allen R. The LILR family: modulators of innate and adaptive immune pathways in health and disease. Tissue antigens. 2004; 64: 215–225. doi: 10.1111/j.0001-2815.2004.00290.x.
  56. Sedlacek A.L., Gerber S.A., Randall T.D. et al. Ge­neration of a dual-functioning antitumor immune response in the peritoneal cavity. Am. J. Pathol. 2013; 183 (4): 1318–1328. doi: 10.1016/j.ajpath.2013.06.030.
  57. Yokota S.J., Facciponte J.G., Kelleher R.J.Jr. et al. Changes in ovarian tumor cell number, tumor vasculature, and T cell function monitored in vivo using a novel xenograft model. Cancer Immun. 2013; 13: 11. PMID: 23885217.
  58. Titov K.S., Demidov L.V., Shubina I.Zh. et al. Clinical efficiency of intra-cavity biotherapy patients with malignant effusions. Rossiyskiy onkologicheskiy zhurnal. 2015; (2): 8–12. (In Russ.)
  59. Nerodo G.A., Novikova I.A., Zlatnik E.Yu. et al. Application of ingaron in combination with chemotherapy in patients with stage III–IV ovarian cancer. Fundamentalʹnye issledova­niya. 2015; (1–8): 1649–1654. (In Russ.)
  60. Kulbe H., Chakravarty P., Leinster D.A. et al. A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. Cancer Res. 2012; 72: 66–75. doi: 10.1158/0008-5472.CAN-11-2178.

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