Volume 25, Issue 1 (1-2021)                   ibj 2021, 25(1): 1-7 | Back to browse issues page

PMID: 33129234

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Herein, we review the current findings of how a variety of accessory cells could participate in shaping the tumor microenvironment and supporting the mechanisms by which cancer cells undertake the epithelial-mesenchymal transition (EMT). EMT, a complex of phenotypic changes, promotes cancer cell invasion and creates resistance to chemotherapies. Among the accessory cells present in the EMT, immune cells (both native and adaptive) can reciprocally influence the tumor cells features, promote EMT and negatively regulate the anticancer immune response. In this review, we look over the role of EMT in crosstalk between tumor cells and the immune system, with specific emphasis on breast tumors. Finally, we suggest that understanding the role of immune cells in cancer progression could create new opportunities for diagnostic and therapeutic interventions in cancer combination therapy.
Type of Study: Review Article | Subject: Cancer Biology

1. Romeo E, Caserta CA, Rumio C, Marcucci F. The vicious cross-talk between tumor cells with an emt phenotype and cells of the immune system. Cells 2019; 8(5): 460. [DOI:10.3390/cells8050460]
2. Plava J, Cihova M, Burikova M, Matuskova M, Kucerova L, Miklikova S. Recent advances in understanding tumor stroma-mediated chemoresistance in breast cancer. Molecular cancer 2019; 18(1): 67. [DOI:10.1186/s12943-019-0960-z]
3. Barriga V, Kuol N, Nurgali K, Apostolopoulos V. The complex interaction between the tumor micro-environment and immune checkpoints in breast cancer. Cancers (Basel) 2019; 11(8): 1205. [DOI:10.3390/cancers11081205]
4. Jiang Y, Zhan H. Communication between EMT and PD-L1 signaling: New insights into tumor immune evasion. Cancer letters 2020; 468: 72-81. [DOI:10.1016/j.canlet.2019.10.013]
5. Chockley PJ, Keshamouni VG. Immunological consequences of epithelial-mesenchymal transition in tumor progression. Jurnal of immunology 2016; 197(3): 691-698. [DOI:10.4049/jimmunol.1600458]
6. De Matteis S, Canale M, Verlicchi A, Bronte G, Delmonte A, Crinò L, Martinelli G, Ulivi P. Advances in molecular mechanisms and immunotherapy involving the immune cell-promoted epithelial-to-mesenchymal transition in lung cancer. Journal of oncology 2019; Article ID 7475364. [DOI:10.1155/2019/7475364]
7. Son H, Moon A. Epithelial-mesenchymal transition and cell invasion. Toxicological research 2010; 26(4): 245-252. [DOI:10.5487/TR.2010.26.4.245]
8. Konradi S, Yasmin N, Haslwanter D, Weber M, Gesslbauer B, Sixt M, Strobl H. Langerhans cell maturation is accompanied by induction of N-cadherin and the transcriptional regulators of epithelial-mesenchymal transition ZEB1/2. European journal of immunology 2014; 44(2): 553-560. [DOI:10.1002/eji.201343681]
9. Teeuwssen M, Fodde R. Cell heterogeneity and phenotypic plasticity in metastasis formation: The case of colon cancer. Cancers (Basel) 2019; 11(9): 1368. [DOI:10.3390/cancers11091368]
10. Nahas GR, Patel SA, Bliss SA, Rameshwar P. Can breast cancer stem cells evade the immune system? Current medicinal chemistry 2012; 19(35): 6036-6049. [DOI:10.2174/092986712804485863]
11. Ferrari SM, Fallahi P, Galdiero MR, Ruffilli I, Elia G, Ragusa F, Rosaria Paparo S, Patrizio A, Mazzi V, Varricchi G, Marone G, Antonelli A. Immune and inflammatory cells in thyroid cancer microenvironment. International journal of molecular sciences 2019; 20(18): 4413. [DOI:10.3390/ijms20184413]
12. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331(6024): 1565-1570. [DOI:10.1126/science.1203486]
13. Cantoni C, Huergo-Zapico L, Parodi M, Pedrazzi M, Mingari MC, Moretta A, et al. NK cells, tumor cell transition, and tumor progression in solid malignancies: New hints for NK-based immunotherapy? Journal of immunology research 2016; 2016: 4684268. [DOI:10.1155/2016/4684268]
14. Liu J, Li C, Zhang L, Liu K, Jiang X, Wang X, Yang L, Liang W, Liu K, Hu J, Li F. Association of tumour-associated macrophages with cancer cell EMT, invasion, and metastasis of Kazakh oesophageal squamous cell cancer. Diagnostic pathology 2019; 14: 55. [DOI:10.1186/s13000-019-0834-0]
15. Chae YK, Chang S, Ko T, Anker J, Agte S, Iams W, Choi WM, Lee K, Cruz M. Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC). Scientific reports 2018; 8(1): 2918. [DOI:10.1038/s41598-018-21061-1]
16. Dominguez C, David JM, Palena C. Epithelial-mesenchymal transition and inflammation at the site of the primary tumor. Seminars in cancer biology 2017; 47: 177-184. [DOI:10.1016/j.semcancer.2017.08.002]
17. Ke X, Chen C, Song Y, Cai Q, Li J, Tang Y, Han XU, QU W, Chen A, Wang H, XU G, Liu D. Hypoxia modifies the polarization of macrophages and their inflammatory microenvironment, and inhibits malignant behavior in cancer cells. Oncology letters 2019; 18(6): 5871-5878. [DOI:10.3892/ol.2019.10956]
18. Ruytinx P, Proost P, Van Damme J, Struyf S. Chemokine-induced macrophage polarization in inflammatory conditions. Frontiers in immunology 2018; 9: 1930. [DOI:10.3389/fimmu.2018.01930]
19. Xuan W, Qu Q, Zheng B, Xiong S, Fan GH. The chemotaxis of M1 and M2 macrophages is regulated by different chemokines. Journal of leukocyte biology 2015; 97(1): 61-69. [DOI:10.1189/jlb.1A0314-170R]
20. Su S, Liu Q, Chen J, Chen J, Chen F, He C, Huang D, Wu W, Lin L, Huang W, Zhang J, Cui X, Zheng F, Li H, Yao H, Su F, Song E. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer cell 2014; 25(5): 605-620. [DOI:10.1016/j.ccr.2014.03.021]
21. Lu S, Li D, Xi L, Calderone R. Interplay of interferon-gamma and macrophage polarization during Talaromyces marneffei infection. Microbial pathogenesis 2019; 134: 103594. [DOI:10.1016/j.micpath.2019.103594]
22. Sousa S, Brion R, Lintunen M, Kronqvist P, Sandholm J, Mönkkönen J, Kellokumpu-Lehtinen PL, Lauttia S, Tynninen O, Joensuu H, Heymann D, Maatta JA. Human breast cancer cells educate macrophages toward the M2 activation status. Breast cancer research 2015; 17: 101. [DOI:10.1186/s13058-015-0621-0]
23. Raschioni C, Bottai G, Sagona A, Errico V, Testori A, Gatzemeier W, Corsi F, Tinterri C, Roncalli M, Santarpia L, Tommaso LD. CXCR4/CXCL12 signaling and protumor macrophages in primary tumors and sentinel lymph nodes are involved in luminal B breast cancer progression. Disease markers 2018; 2018: 5018671. [DOI:10.1155/2018/5018671]
24. Guo S, Deng CX. Effect of stromal cells in tumor microenvironment on metastasis initiation. International Journal of biological sciences 2018; 14(14): 2083-2093. [DOI:10.7150/ijbs.25720]
25. ElShamy WM, Sami E, Paul BT, Koziol JA. The immunosuppressive microenvironment in BRCA1-IRIS-overexpressing TNBC tumors is induced by bidirectional interaction with tumor-associated macrophages. Cancer research 2020; DOI: 10.1158/ 0008-5472.CAN-19-2374.
26. Jézéquel P, Campion L, Spyratos F, Loussouarn D, Campone M, Guerin-Charbonnel C, Joalland MP, André J, Descotes F, Grenot C, Roy P, Carlioz A, Martin PM, Chassevent A, Jourdan Ml, Ricolleau G. Validation of tumor-associated macrophage ferritin light chain as a prognostic biomarker in node-negative breast cancer tumors: A multicentric 2004 national PHRC study. International journal of cancer 2012; 131(2): 426-437. [DOI:10.1002/ijc.26397]
27. Hussein MR, Hassan HI. Analysis of the mononuclear inflammatory cell infiltrate in the normal breast, benign proliferative breast disease, in situ and infiltrating ductal breast carcinomas: preliminary observations. Journal of clinical pathology 2006; 59(9): 972-977. [DOI:10.1136/jcp.2005.031252]
28. Maimela NR, Liu S, Zhang Y. Fates of CD8+ T cells in Tumor Microenvironment. Computational and structural biotechnology journal 2019; 17:1-13. [DOI:10.1016/j.csbj.2018.11.004]
29. Buisseret L, Pommey S, Allard B, Garaud S, Bergeron M, Cousineau I, Ameye L, Bareche Y, Paesmans M, Crown JPA, Di Leo A, Loi S, Piccart, Gebhart M, Willard Gallo K, Sotiriou C, Stagg J. Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial. Annals of oncology 2018; 29(4): 1056-1062. [DOI:10.1093/annonc/mdx730]
30. Neo SY, Yang Y, Record J, Ma R, Chen X, Chen Z, Tobin NP, Blake E, Seitz C, Thomas R, Wagner AK, Andersson J, de Boniface J, Bergh J, Murray S, Alici E, Childs R, Johansson M, Westerberg LS, Haglund F, Hartman J, Lundqvist J CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment. Journal of clinical investigation 2020; 130(3): 1185-1198. [DOI:10.1172/JCI128895]
31. Tower H, Ruppert M, Britt K. The immune microenvironment of breast cancer progression. Cancers (Basel) 2019; 11(9): 1375. [DOI:10.3390/cancers11091375]
32. Zhang S. The role of transforming growth factor β in T helper 17 differentiation. Immunology 2018; 155(1): 24-35. [DOI:10.1111/imm.12938]
33. Wu X, Tian J, Wang S. Insight into non-pathogenic th17 cells in autoimmune diseases. Frontiers in immunology 2018; 9: 1112. [DOI:10.3389/fimmu.2018.01112]
34. Cserni G, Serfozo O, Ambrózay E, Markó L, Krenács L. Spontaneous pathological complete regression of high-grade triple-negative breast cancer with axillary metastasis. Polish journal of pathology 2019; 70(2):139-143. [DOI:10.5114/pjp.2019.87105]
35. Brochez L, Meireson A, Chevolet I, Sundahl N, Ost P, Kruse V. Challenging PD-L1 expressing cytotoxic T cells as a predictor for response to immunotherapy in melanoma. Nature communications 2018; 9(1): 1-3. [DOI:10.1038/s41467-018-05047-1]
36. Ma J, Gao S, Xie X, Sun E, Zhang M, Zhou Q, Lu C. Sparc inhibits breast cancer bone metastasis and may be a clinical therapeutic target. Oncology letters 2017; 14: 5876-5882. [DOI:10.3892/ol.2017.6925]
37. Planes-Laine G, Rochigneux P, Bertucci F, Chrétien AS, Viens P, Sabatier R, Gonçalves A. PD-1/PD-L1 targeting in breast cancer: the first clinical evidences are emerging-a literature review. Cancers. 2019; 11: 1033. [DOI:10.3390/cancers11071033]
38. Barclay J, Creswell J, León J. Cancer immunotherapy and the PD-1/PD-L1 checkpoint pathway. Archivos espanoles de urologia 2018; 71(4): 393-399.
39. Lou J, Zhou Y, Huang J, Qian X. Relationship between PD-L1 expression and clinical characteristics in patients with breast invasive ductal carcinoma. Open medicine 2017; 12(1): 288-292. [DOI:10.1515/med-2017-0042]
40. Turcotte M, Allard D, Mittal D, Bareche Y, Buisseret L, José V, Pommey S, Delisle V, Loi S, Joensuuu H, Kellokumpu-Lehtinen PL, Sotiriou C, Smyth MJ, Stagg J. Cd73 promotes resistance to her2/erbb2 antibody therapy. Cancer research 2017; 77(20): 5652-5663. [DOI:10.1158/0008-5472.CAN-17-0707]
41. Nair S, Dhodapkar MV. Natural killer t cells in cancer immunotherapy. Frontiers in immunology 2017; 8: 1178. [DOI:10.3389/fimmu.2017.01178]
42. Krijgsman D, Hokland M, Kuppen PJK. The role of natural killer T cells in cancer-a phenotypical and functional approach. Frontiers in immunology 2018; 9: 367. [DOI:10.3389/fimmu.2018.00367]
43. Pilones KA, Kawashima N, Yang AM, Babb JS, Formenti SC, Demaria S. Invariant natural killer T cells regulate breast cancer response to radiation and CTLA-4 blockade. Clinical cancer research 2009; 15(2): 597-606. [DOI:10.1158/1078-0432.CCR-08-1277]
44. Okita R, Shimizu K, Nakata M. Epithelial-mesenchymal transition-induced metastasis could be a bait for natural killer cells. Journal of thoracic disease 2018; 10(Suppl 26): S3143-S3146. [DOI:10.21037/jtd.2018.08.19]
45. Chockley PJ, Chen J, Chen G, Beer DG, Standiford TJ, Keshamouni VG. Epithelial-mesenchymal transition leads to NK cell-mediated metastasis-specific immunosurveillance in lung cancer. The Journal of clinical investigation 2018; 128(4):1384-1396. [DOI:10.1172/JCI97611]
46. Chockley P, Keshamouni V. Metastasis-specific, NK cell-mediated, immune surveillance of lung cancer. The journal of immunology 2018; 200(1 Supplement): 124.8.
47. Poli A, Michel T, Thérésine M, Andrès E, Hentges F, Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset. Immunology 2009; 126(4): 458-465. [DOI:10.1111/j.1365-2567.2008.03027.x]
48. Mukherjee N, Ji N, Hurez V, Curiel TJ, Montgomery MO, Braun AJ, Nicolas M, Aquilera M, Kaushik D, Liu Q, Ruan J, Kendrick KA, Svatek RS. Intratumoral CD56bright natural killer cells are associated with improved survival in bladder cancer. Oncotarget 2018; 9(92): 36492-36502. [DOI:10.18632/oncotarget.26362]
49. Lecot P, Sarabi M, Pereira Abrantes M, Mussard J, Koeanderman L, Caux C, Bendriss- Vermare N, Michallet mc. Neutrophil heterogeneity in cancer: from biology to therapies. Frontiers in immunology 2019; 10: 2155. [DOI:10.3389/fimmu.2019.02155]
50. Lorenzo-Herrero S, López-Soto A, Sordo-Bahamonde C, Gonzalez-Rodriguez AP, Vitale M, Gonzalez S. NK cell-based immunotherapy in cancer metastasis. Cancers 2019; 11: 29. [DOI:10.3390/cancers11010029]
51. Peltanova B, Raudenska M, Masarik M. Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review. Molecular cancer 2019; 18(1): 63. [DOI:10.1186/s12943-019-0983-5]
52. Vitale M, Cantoni C, Pietra G, Mingari MC, Moretta L. Effect of tumor cells and tumor microenvironment on NK‐cell function. European journal of immunology 2014; 44(6): 1582-1592. [DOI:10.1002/eji.201344272]
53. Roato I, Vitale M. The uncovered role of immune cells and NK cells in the regulation of bone metastasis. Frontiers in endocrinology (Lausanne) 2019; 10: 145. [DOI:10.3389/fendo.2019.00145]
54. Masucci MT, Minopoli M, Carriero MV. Tumor associated neutrophils. their role in tumorigenesis, metastasis, prognosis and therapy. Frontiers in oncology 2019; 9: 1146. [DOI:10.3389/fonc.2019.01146]
55. Mizuno R, Kawada K, Itatani Y, Ogawa R, Kiyasu Y, Sakai Y. The role of tumor-associated neutrophils in colorectal cancer. International journal of molecular sciences 2019; 20: 529. [DOI:10.3390/ijms20030529]
56. Leach J, Morton JP, Sansom OJ. Neutrophils: homing in on the myeloid mechanisms of metastasis. Molecular immunology 2019; 110: 69-76. [DOI:10.1016/j.molimm.2017.12.013]
57. Grenier A, Dehoux M, Boutten A, Arce-Vicioso M, Durand Gv, Gougerot-Pocidalo MA, Chollet-Martin S. Oncostatin M production and regulation by human polymorphonuclear neutrophils. Blood 1999; 93(4): 1413-1421. [DOI:10.1182/blood.V93.4.1413]
58. Lauber S, Wong S, Cutz JC, Tanaka M, Barra N, Lhoták S, Ashkar A, Douglas Richards C. Novel function of Oncostatin M as a potent tumour‐promoting agent in lung. International journal of cancer 2015; 136(4): 831-843. [DOI:10.1002/ijc.29055]
59. Wu L, Saxena S, Awaji M, Singh RK. Tumor-associated neutrophils in cancer: going pro. Cancers 2019; 11: 564. [DOI:10.3390/cancers11040564]
60. Zhang X, Zhang W, Yuan X, Fu M, Qian H, Xu W. Neutrophils in cancer development and progression: roles, mechanisms, and implications. International journal of oncology 2016; 49(3): 857-867. [DOI:10.3892/ijo.2016.3616]
61. Katsura A, Tamura Y, Hokari S, Harada M, Morikawa M, Sakurai T, Takahashi K, Mizutani A, Nishida J, Yokoyma Y, Morishita V, Murakami T, Ehata S, Miyazono K, Koinuma D. ZEB1-regulated inflammatory phenotype in breast cancer cells. Molecular oncology 2017; 11(9): 1241-1262. [DOI:10.1002/1878-0261.12098]
62. Zhu H, Gu Y, Xue Y, Yuan M, Cao X, Liu Q. CXCR2+ MDSCs promote breast cancer progression by inducing EMT and activated T cell exhaustion. Oncotarget 2017; 8(70):114554-114567. [DOI:10.18632/oncotarget.23020]
63. Gabrilovich DI. Myeloid-derived suppressor cells. Cancer immunology research 2017; 5(1): 3-8. [DOI:10.1158/2326-6066.CIR-16-0297]
64. Chiodoni C, Sangaletti S, Colombo MP. Matricellular proteins tune myeloid-derived suppressor cell recruitment and function in breast cancer. Journal of leukocyte biology 2017; 102(2): 287-292. [DOI:10.1189/jlb.3MR1016-447R]
65. Sangaletti S, Tripodo C, Santangelo A, Castioni N, Portararo P, Gulino A, Botti L, Parenza M, Cappetti B, Orlandi R, Tagliabud E, Chiodoni C, Colombo MP. Mesenchymal transition of high-grade breast carcinomas depends on extracellular matrix control of myeloid suppressor cell activity. Cell reports 2016; 17(1): 233-248. [DOI:10.1016/j.celrep.2016.08.075]
66. Sangaletti S, Talarico G, Chiodoni C, Cappetti B, Botti L, Portararo P, Gulino A, Maria Consonni F, Sica A, Ranson G, Di Nicola M, Tripodo C, Colombo M. Sparc is a new myeloid-derived suppressor cell marker licensing suppressive activities. Frontiers in immunology 2019; 10: 1369. [DOI:10.3389/fimmu.2019.01369]
67. Yu F, Shi Y, Wang J, Li J, Fan D, Ai W. Deficiency of Kruppel-like factor KLF4 in mammary tumor cells inhibits tumor growth and pulmonary metastasis and is accompanied by compromised recruitment of myeloid-derived suppressor cells. International journal of cancer 2013; 133(12): 2872-2883. [DOI:10.1002/ijc.28302]
68. Cheng Y, Ma XL, Wei YQ, Wei XW. Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochimica et biophysica acta reviews on cancer 2019; 1871(2): 289-312. [DOI:10.1016/j.bbcan.2019.01.005]
69. Umansky V, Blattner C, Gebhardt C, Utikal J. The role of myeloid-derived suppressor cells (MDSC) in cancer progression. Vaccines (Basel) 2016; 4(4): 36. [DOI:10.3390/vaccines4040036]
70. Pinton L, Solito S, Damuzzo V, Francescato S, Pozzuoli A, Berizzi A, Mocellin S, Rossi CR, Bronte V, Mandruzzato S. Activated T cells sustain myeloid-derived suppressor cell-mediated immune suppression. Oncotarget 2016; 7(2): 1168-1184. [DOI:10.18632/oncotarget.6662]
71. Ostrand-Rosenberg S, Horn LA, Haile ST. The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. Journal of immunology 2014; 193(8): 3835-3841. [DOI:10.4049/jimmunol.1401572]
72. Singh S, Mehta N, Lilan J, Budhthoki MB, Chao F, Yong L. Initiative action of tumor-associated macrophage during tumor metastasis. Biochimie open 2017; 4: 8-18. [DOI:10.1016/j.biopen.2016.11.002]
73. Ma X, Wang M, Yin T, Zhao Y, Wei X. Myeloid-derived suppressor cells promote metastasis in breast cancer after the stress of operative removal of the primary cancer. Frontiers in oncology 2019; 9: 855. [DOI:10.3389/fonc.2019.00855]