Skip to main content
SpringerLink
Log in

Heterogeneity and Plasticity of Immune Inflammatory Responses in the Tumor Microenvironment: Their Role in the Antitumor Effect and Tumor Aggressiveness

  • Published:
Biology Bulletin Reviews Aims and scope Submit manuscript

Abstract

This review considers the role that immune inflammatory responses (IIRs) play in tumor development and progression. Intratumoral IIR heterogeneity is presumably due to simultaneous differentiation and activation of certain T helper (Th) subpopulations and macrophages in various loci of the tumor, their phenotypic plasticity, and their antagonism of Th1 and Th2 responses. Evidence is provided to demonstrate that the IIR type in the tumor microenvironment determines the probability of the epithelial–mesenchymal transition (EMT), the emergence of invasive properties in tumor cells, the formation of tumor and premetastatic niches, and chemosensitivity. It is hypothesized that the effect of IIRs on tumor cells depends on the IIR type, which determines the cell and cytokine spectrum in the tumor microenvironment, rather than on the efficiency of specific immune responses to tumor antigens. Lastly, it is assumed that more efficient targets for IIR guidance are not provided by single molecules, but rather by the signaling pathways that can permanently prevent the Th2-type IIRs or suppress inflammatory reactions in the tumor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

REFERENCES

  1. Addeo, R., A new frontier for targeted therapy in NSCLC: clinical efficacy of pembrolizumab in the inhibition of programmed cell death 1 (PD-1), Exp. Rev. Anticancer Ther., 2017, vol. 17, no. 3, pp. 199–201.

    Article  CAS  Google Scholar 

  2. Akdis, M., Palomares, O., Veen van de, W., Splunter van, M., and Akdis, C.A., TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection, Allergy Clin. Immunol., 2012, vol. 129, no. 6, pp. 1438–1449.

    Article  CAS  Google Scholar 

  3. Allavena, P., Sica, A., Garlanda, C., and Mantovani, A., The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance, Immunol. Rev., 2008, vol. 222, pp. 155–161.

    Article  PubMed  CAS  Google Scholar 

  4. Arnold, K.M., Opdenaker, L.M., Flynn, D., and Sims-Mourtada, J., Wound healing and cancer stem cells: inflammation as a driver of treatment resistance in breast cancer, Cancer Growth Metastasis, 2015, vol. 8, pp. 1–13.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Barcellos-Hoff, M.H., Lyden, D., and Wang, T.C., The evolution of the cancer niche during multistage carcinogenesis, Nat. Rev. Cancer, 2013, vol. 13, no. 7, pp. 511–518.

    Article  PubMed  CAS  Google Scholar 

  6. Barrientos, S., Stojadinovic, O., Golinko, M.S., Brem, H., and Tomic-Canic, M., Growth factors and cytokines in wound healing, Wound Repair Regener., 2008, vol. 16, no. 5, pp. 585–601.

    Article  Google Scholar 

  7. Bates, R.C., DeLeo, M.J., and Mercurio, A.M., The epithelial-mesenchymal transition of colon carcinoma involves expression of IL-8 and CXCR-1-mediated chemotaxis, Exp. Cell. Res., 2004, vol. 299, no. 2, pp. 315–324.

    Article  PubMed  CAS  Google Scholar 

  8. Ben-Sasson, S.Z., Hu-Li, J., Quiel, J., Cauchetaux, S., Ratner, M., Shapira, I., Dinarello, C.A., and Paul, W.E., IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation, Proc. Natl. Acad. Sci. U.S.A., 2009, vol. 106, no. 17, pp. 7119–7124.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bernink, J.H., Peters, C.P., Munneke, M., te Velde, A.A., Meijer, S.L., Weijer, K., Hreggvidsdottir, H.S., Heinsbroek, S.E., Legrand, N., Buskens, C.J., Bemelman, W.A., Mjösberg, J.M., and Spits, H., Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues, Nat. Immunol., 2013, vol. 14, no. 3, pp. 221–229.

    Article  PubMed  CAS  Google Scholar 

  10. Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T.B., Oukka, M., Weiner, H.L., and Kuchroo, V.K., Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells, Nature, 2006, vol. 441, no. 7090, pp. 235–238.

    Article  PubMed  CAS  Google Scholar 

  11. Bhowmick, N.A., Neilson, E.G., and Moses, H.L., Stromal fibroblasts in cancer initiation and progression, Nature, 2004, vol. 432, no. 7015, pp. 332–337.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Bilate, A.M. and Lafaille, J.J., Induced CD4+Foxp3+ regulatory T cells in immune tolerance, Annu. Rev. Immunol., 2012, vol. 30, pp. 733–758.

    Article  PubMed  CAS  Google Scholar 

  13. Bluestone, J.A., Mackay, C.R., O’Shea, J.J., and Stockinger, B., The functional plasticity of T cell subsets, Nat. Rev. Immunol., 2009, vol. 9, no. 11, pp. 811–816.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Brabletz, T., Hlubek, F., Spaderna, S., Schmalhofer, O., Hiendlmeyer, E., Jung, A., and Kirchner, T., Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin, Cells Tissues Organs, 2005, vol. 179, nos. 1–2, pp. 56–65.

  15. Bricard, G., Cesson, V., Devevre, E., Bouzourene, H., Barbey, C., Rufer, N., Im, J.S., Alves, P.M., Martinet, O., Halkic, N., Cerottini, J.C., Romero, P., Porcelli, S.A., Macdonald, H.R., and Speiser, D.E., Enrichment of human CD4+ Vα24/Vβ11 invariant NKT cells in-intrahepatic malignant tumors, J. Immunol., 2009, vol. 182, no. 8, pp. 5140–5151.

    Article  PubMed  CAS  Google Scholar 

  16. Bronte, V., Serafini, P., Mazzoni, A., Segal, D.M., and Zanovello, P., L-arginine metabolism in myeloid cells controls T-lymphocyte functions, Trends Immunol., 2003, vol. 24, no. 6, pp. 302–306.

    Article  PubMed  CAS  Google Scholar 

  17. Bruchard, M., Rebé, C., Derangere, V., Togbé, D., Ryffel, B., Boidot, R., Humblin E., Hamman, A., Chalmin, F., Berger, H., Chevriaux, A., Limagne, E., Apetoh, L., Végran, F., and Ghiringhelli, F., The receptor NLRP3 is a transcriptional regulator of TH2 differentiation, Nat. Immunol., 2015, vol. 16, no. 8, pp. 859–870.

    Article  PubMed  CAS  Google Scholar 

  18. Caramalho, I., Lopes-Carvalho, T., Ostler, D., Zelenay, S., Haury, M., and Demengeot, J., Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide, J. Exp. Med., 2003, vol. 197, no. 4, pp. 403–411.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Chaux, P., Moutet, M., Faivre, J., Martin, F., and Martin, M., Inflammatory cells infiltrating human colorectal carcinomas express HLA class II but not B7–1 and B7–2 costimulatory molecules of the T-cell activation, Lab. Invest., 1996, vol. 74, no. 5, pp. 975–983.

    PubMed  CAS  Google Scholar 

  20. Chen, X., Oppenheim, J.J., Winkler-Pickett, R.T., Ortaldo, J.R., and Howard, O.M., Glucocorticoid amplifies IL-2-dependent expansion of functional FoxP3+CD4+CD25+ T regulatory cells in vivo and enhances their capacity to suppress EAE, Eur. J. Immunol., 2006, vol. 36, no. 8, pp. 2139–2149.

    Article  PubMed  CAS  Google Scholar 

  21. Chen, X., Bäumel, M., Männel, D.N., Howard, O.M., and Oppenheim, J.J., Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells, J. Immunol., 2007, vol. 179, no. 1, pp. 154–161.

    Article  PubMed  CAS  Google Scholar 

  22. Cózar, J.M., Canton, J., Tallada, M., Concha, A., Cabrera, T., Garrido, F., and Ruiz-Cabello Osuna, F., Analysis of NK cells and chemokine receptors in tumor infiltrating CD4 T lymphocytes in human renal carcinomas, Cancer Immunol., Immunother., 2005, vol. 54, no. 9, pp. 858–866.

    Article  CAS  Google Scholar 

  23. Crellin, N.K., Garcia, R.V., Hadisfar, O., Allan, S.E., Steiner, T.S., and Levings, M.K., Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells, J. Immunol., 2005, vol. 175, no. 12, pp. 8051–8059.

    Article  PubMed  CAS  Google Scholar 

  24. Crome, S.Q., Clive, B., Wang, A.Y., Kang, C.Y., Chow, V., Yu, J., Lai, A., Ghahary, A., Broady, R., and Levings, M.K., Inflammatory effects of ex vivo human Th17 cells are suppressed by regulatory T cells, J. Immunol., 2010, vol. 185, no. 6, pp. 3199–3208.

    Article  PubMed  CAS  Google Scholar 

  25. Cui, Y.L., Li, H.K., Zhou, H.Y., Zhang, T., and Li, Q., Correlations of tumor-associated macrophage subtypes with liver metastases of colorectal cancer, Asian Pac. J. Cancer Prev., 2013, vol. 14, no. 2, pp. 1003–1007.

    Article  PubMed  Google Scholar 

  26. Das, A., Sinha, M., Datta, S., Abas, M., Chaffee, S., Sen, C.K., and Roy, S., Monocyte and macrophage plasticity in tissue repair and regeneration, Am. J. Pathol., 2015, vol. 185, no. 10, pp. 2596–2606.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. De Wever, O., Demetter, P., Mareel, M., and Bracke, M., Stromal myofibroblasts are drivers of invasive cancer growth, Int. J. Cancer, 2008a, vol. 123, no. 10, pp. 2229–2238.

    Article  PubMed  CAS  Google Scholar 

  28. De Wever, O., Pauwels, P., De Craene, B., Sabbah, M., Emami, S., Redeuilh, G., Gespach, C., Bracke, M., and Berx, G., Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion front, Histochem. Cell Biol., 2008b, vol. 130, no. 3, pp. 481–494.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. DeNardo, D.G., Barreto, J.B., Andreu, P., Vasquez, L., Tawfik, D., Kolhatkar, N., and Coussens, L.M., CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages, Cancer Cell, 2009, vol. 16, no. 2, pp. 91–102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. DeNardo, D.G., Brennan, D.J., Rexhepaj, E., Ruffell, B., Shiao, S.L., Madden, S.F., Gallagher, W.M., Wadhwani, N., Keil, S.D., Junaid, S.A., Rugo, H.S., Hwang, E.S., Jirström, K., West, B.L., and Coussens, L.M., Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy, Cancer Discovery, 2011, vol. 1, no. 1, pp. 54–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Denkert, C., Loibl, S., Noske, A., Roller, M., Müller, B.M., Komor, M., Budczies, J., Darb-Esfahani, S., Kronenwett, R., Hanusch, C., von Törne, C., Weichert, W., Engels, K., Solbach, C., Schrader, I., et al., Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer, J. Clin. Oncol., 2010, vol. 28, no. 1, pp. 105–113.

    Article  PubMed  CAS  Google Scholar 

  32. Denkert, C., von Minckwitz, G., Brase, J.C., Sinn, B.V., Gade, S., et al., Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers, J. Clin. Oncol., 2015, vol. 33, no. 9, pp. 983–991.

    Article  PubMed  CAS  Google Scholar 

  33. Diehl, S. and Rincón, M., The two faces of IL-6 on Th1/Th2 differentiation, Mol. Immunol., 2002, vol. 39, no. 9, pp. 531–536.

    Article  PubMed  CAS  Google Scholar 

  34. Dieu-Nosjean, M.C., Goc, J., Giraldo, N.A., Sautès-Fridman, C., and Fridman, W.H., Tertiary lymphoid structures in cancer and beyond, Trends Immunol., 2014, vol. 35, no. 11, pp. 571–580.

    Article  PubMed  CAS  Google Scholar 

  35. Dong, H., Strome, S.E., Salomao, D.R., Tamura, H., Hirano, F., Flies, D.B., Roche, P.C., Lu, J., Zhu, G., Tamada, K., Lennon, V.A., Celis, E., and Chen, L., Tumor-associated B7–H1 promotes T-cell apoptosis: a potential mechanism of immune evasion, Nat. Med., 2002, vol. 8, no. 8, pp. 793–800.

    Article  PubMed  CAS  Google Scholar 

  36. Dulos, J., Carven, G. J., van Boxtel, S.J., Evers, S., Driessen-Engels, L.J., Hobo, W., Gorecka, M.A., de Haan, A.F., Mulders, P., Punt, C.J., Jacobs, J.F., Schalken, J.A., Oosterwijk, E., Eenennaam van, H., and Boots, A.M., PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer, J. Immunother., 2012, vol. 35, no. 2, pp. 169–178.

    Article  PubMed  CAS  Google Scholar 

  37. Edin, S., Wikberg, M.L., Dahlin, A.M., Rutegard, J., Oberg, A., Oldenborg, P.-A., and Palmqvist, R., The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer, PLoS One, 2012, vol. 7, no. 10, p. e47045.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Eiró, N., Pidal, I., Fernandez-Garcia, B., Junquera, S., Lamelas, M.L., del Casar, J.M., González, L.O., López-Muñiz, A., and Vizoso, F.J., Impact of CD68/(CD3+CD20) ratio at the invasive front of primary tumors on distant metastasis development in breast cancer, PLoS One, 2012, vol. 7, no. 12, p. e52796.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Elinav, E., Nowarski, R., Thaiss, C.A., Hu, B., Jin, C., and Flavell, R.A., Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms, Nat. Rev. Cancer, 2013, vol. 13, no. 11, pp. 759–771.

    Article  PubMed  CAS  Google Scholar 

  40. Eming, S.A., Krieg, T., and Davidson, J.M., Inflammation in wound repair: molecular and cellular mechanisms, J. Invest. Dermatol., 2007, vol. 127, no. 3, pp. 514–525.

    Article  PubMed  CAS  Google Scholar 

  41. Erez, N., Truitt, M., Olson, P., Arron, S.T., and Hanahan, D., Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner, Cancer Cell, 2010, vol. 17, no. 2, pp. 135–147.

    Article  PubMed  CAS  Google Scholar 

  42. Esche, C., Lokshin, A., Shurin, G.V., Gastman, B.R., Rabinowich, H., Watkins, S.C., Lotze, M.T., Shurin, M.R., Tumor’s other immune targets: dendritic cells, J. Leukocyte Biol., 1999, vol. 66, no. 2, pp. 336–344.

    Article  PubMed  CAS  Google Scholar 

  43. Fenchel, K., Sellmann, L., and Dempke, W.C.M., Overall survival in non-small cell lung cancer—what is clinically meaningful? Transl. Lung Cancer Res., 2016, vol. 5, no. 1, pp. 115–119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Fernando, R.I., Castillo, M.D., Litzinger, M., Hamilton, D.H., and Palena, C., IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells, Cancer Res., 2011, vol. 71, no. 15, pp. 5296–5306.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Ferrante, C.J. and Leibovich, S.J., Regulation of macrophage polarization and wound healing, Adv. Wound Care, 2012, vol. 1, no. 1, pp. 10–16.

    Article  Google Scholar 

  46. Fridlender, Z.G., Sun, J., Kim, S., Kapoor, V., Cheng, G., Ling, L., Worthen, G.S., and Albelda, S.M., Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN, Cancer Cell, 2009, vol. 16, no. 3, pp. 183–194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Fridman, W.H., Pagès, F., Sautès-Fridman, C., and Galon, J., The immune contexture in human tumors: impact on clinical outcome, Nat. Rev. Cancer, 2012, vol. 12, no. 4, pp. 298–306.

    Article  PubMed  CAS  Google Scholar 

  48. Friedl, P. and Alexander, S., Cancer invasion and the microenvironment: plasticity and reciprocity, Cell, 2011, vol. 147, no. 5, pp. 992–1009.

    Article  PubMed  CAS  Google Scholar 

  49. Gaggioli, C., Hooper, S., Hidalgo-Carcedo, C., Grosse, R., Marshall, J.F., Harrington, K., and Sahai, E., Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells, Nat. Cell Biol., 2007, vol. 9, no. 12, pp. 1392–1400.

    Article  PubMed  CAS  Google Scholar 

  50. Galon, J., Bindea, G., Mlecnik, B., Angell, H., Lagorce, C., Todosi, A.M., Berger, A., and Pagès, F., Intratumoral immune microenvironment and survival: the immunoscore, Med. Sci. (Paris), 2014, vol. 30, no. 4, pp. 439–444.

    Article  Google Scholar 

  51. Garcia, M.G., Bayo, J., Bolontrade, M.F., Sganga, L., Malvicini, M., Alaniz, L., Aquino, J.B., Fiore, E., Rizzo, M.M., Rodriguez, A., Lorenti, A., Andriani, O., Podhajcer, O., and Mazzolini, G., Hepatocellular carcinoma cells and their fibrotic microenvironment modulate bone marrow-derived mesenchymal stromal cell migration in vitro and in vivo, Mol. Pharm., 2011, vol. 8, no. 5, pp. 1538–1548.

    Article  PubMed  CAS  Google Scholar 

  52. Gerashchenko, T.S., Denisov, E.V., Litviakov, N.V., Zavyalova, M.V., Vtorushin, S.V., Tsyganov, M.M., Perelmuter, V.M., and Cherdyntseva, N.V., Intratumor heterogeneity: nature and biological significance, Biochemistry (Moscow), 2013, vol. 78, no. 11, pp. 1201–1215.

    PubMed  CAS  Google Scholar 

  53. Germain, C., Gnjatic, S., and Dieu-Nosjean, M.C., Tertiary lymphoid structure-associated B cells are key players in anti-tumor immunity, Front. Immunol., 2015, vol. 6, p. 67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Gettinger, S.N., Horn, L., Gandhi, L., Spigel, D.R., Antonia, S.J., et al., Overall survival and long-term safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer, J. Clin. Oncol., 2015, vol. 33, no. 18, pp. 2004–2012.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Ghiringhelli, F., Puig, P.E., Roux, S., Parcellier, A., Schmitt, E., Solary, E., Kroemer, G., Martin, F., Chauffert, B., and Zitvogel, L., Tumor cells convert immature myeloid dendritic cells into TGF-β-secreting cells inducing CD4+CD25+ regulatory T cell proliferation, J. Exp. Med., 2005, vol. 202, no. 7, pp. 919–929.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Gonzalez, D.M. and Medici, D., Signaling mechanisms of the epithelial-mesenchymal transition, Sci. Signaling, 2014, vol. 7, no. 344, p. re8.

    Article  CAS  Google Scholar 

  57. Gorosito Serrán, M., Fiocca Vernengo, F., Beccaria, C.G., Acosta Rodriguez, E.V., Montes, C.L., and Gruppi, A., The regulatory role of B cells in autoimmunity, infections and cancer: perspectives beyond IL10 production, FEBS Lett., 2015, vol. 589, no. 22, pp. 3362–3369.

    Article  PubMed  CAS  Google Scholar 

  58. Gregory, A.D. and Houghton, A.M., Tumor-associated neutrophils: new targets for cancer therapy, Cancer Res., 2011, vol. 71, no. 7, pp. 2411–2416.

    Article  PubMed  CAS  Google Scholar 

  59. Grivennikov, S.I., Greten, F.R., and Karin, M., Immunity, inflammation, and cancer, Cell, 2010, vol. 140, no. 6, pp. 883–899.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Grogan, J.L. and Ouyang, W., A role for Th17 cells in the regulation of tertiary lymphoid follicles, Eur. J. Immunol., 2012, vol. 42, no. 9, pp. 2255–2262.

    Article  PubMed  CAS  Google Scholar 

  61. Gu-Trantien, C. and Willard-Gallo, K., Tumor-infiltrating follicular helper T cells: the new kids on the block, Oncoimmunology, 2013, vol. 2, no. 10, p. e26066.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Hannesdóttir, L., Tymoszuk, P., Parajuli, N., Wasmer, M.H., Philipp, S., Daschil, N., Datta, S., Koller, J.B., Tripp, C.H., Stoitzner, P., Müller-Holzner, E., Wiegers, G.J., Sexl, V., Villunger, A., and Doppler, W., Lapatinib and doxorubicin enhance the Stat1-dependent antitumor immune response, Eur. J. Immunol., 2013, vol. 43, no. 10, pp. 2718–2729.

    Article  PubMed  CAS  Google Scholar 

  63. Heusinkveld, M. and Burg van der, S.H., Identification and manipulation of tumor associated macrophages in human cancers, J. Transl. Med., 2011, vol. 9, pp. 216.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Heusinkveld, M., de Vos van Steenwijk, P.J., Goedemans, R., Ramwadhdoebe, T.H., Gorter, A., Welters, M.J., Hall, T., and van der Burg, S.H., M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells, J. Immunol., 2011, vol. 187, no. 3, pp. 1157–1165.

    Article  PubMed  CAS  Google Scholar 

  65. Hinz, B., Myofibroblasts, Exp. Eye Res., 2016, vol. 142, pp. 56–70.

    Article  PubMed  CAS  Google Scholar 

  66. Huang, Y., Wang, F.M., Wang, T., Wang, Y.J., Zhu, Z.Y., Gao, Y.T., and Du, Z., Tumor-infiltrating FoxP3+ Tregs and CD8+ T cells affect the prognosis of hepatocellular carcinoma patients, Digestion, 2012, vol. 86, no. 4, pp. 329–337.

    Article  PubMed  CAS  Google Scholar 

  67. Im, S.J., Hashimoto, M., Gerner, M.Y., Lee, J., Kissick, H.T., Burger, M.C., Shan, Q., Hale, J.S., Lee, J., Nasti, T.H., Sharpe, A.H., Freeman, G.J., Germain, R.N., Nakaya, H.I., Xue, H.H., and Ahmed, R., Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy, Nature, 2016, vol. 537, no. 7620, pp. 417–421.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Ji, X., Li, J., Xu, L., Wang, W., Luo, M., Luo, S., Ma, L., Li, K., Gong, S., He, L., Zhang, Z., Yang, P., Zhou, Z., Xiang, X., and Wang, C.Y., IL4 and IL-17A provide a Th2/Th17-polarized inflammatory milieu in favor of TGF-β1 to induce bronchial epithelialmesenchymal transition (EMT), Int. J. Clin. Exp. Pathol., 2013, vol. 6, no. 8, pp. 1481–1492.

    PubMed  PubMed Central  CAS  Google Scholar 

  69. Johnson, J.R., Nishioka, M., Chakir, J., Risse, P.A., Almaghlouth, I., Bazarbashi, A.N., Plante, S., Martin, J.G., Eidelman, D., and Hamid, Q., IL-22 contributes to TGF-β1-mediated epithelial-mesenchymal transition in asthmatic bronchial epithelial cells, Respir. Res., 2013, vol. 14, p. 118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Kalluri, R. and Zeisberg, M., Fibroblasts in cancer, Nat. Rev. Cancer, 2006, vol. 6, no. 5, pp. 392–401.

    Article  PubMed  CAS  Google Scholar 

  71. Kaplan, R.N., Riba, R.D., Zacharoulis, S., Bramley, A.H., Vincent, L., Costa, C., MacDonald, D.D., Jin, D.K., Shido, K., Kerns, S.A., Zhu, Z., Hicklin, D., Wu, Y., Port, J.L., Altorki, N., et al., VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche, Nature, 2005, vol. 438, no. 7069, pp. 820–827.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Keibel, A., Singh, V., and Sharma, M.C., Inflammation, microenvironment, and the immune system in cancer progression, Curr. Pharm. Des., 2009, vol. 15, no. 17, pp. 1949–1955.

    Article  PubMed  CAS  Google Scholar 

  73. Kohrt, H.E., Nouri, N., Nowels, K., Johnson, D., Holmes, S., and Lee, P.P., Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer, PLoS Med., 2005, vol. 2, no. 9, p. e284.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Komatsu, N., Mariotti-Ferrandiz, M.E., Wang, Y., Malissen, B., Waldmann, H., and Hori, S., Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity, Proc. Natl. Acad. Sci. U.S.A., 2009, vol. 106, no. 6, pp. 1903–1908.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Krakhmal, N.V., Zavyalova, M.V., Denisov, E.V., Vtorushin, S.V., and Perelmuter, V.M., Invasion of tumor epithelial cells: mechanisms and manifestations, Acta Nat., 2015, vol. 7, no. 2 (25), pp. 18–31.

  76. Kusume, A., Sasahira, T., Luo, Y., Isobe, M., Nakagawa, N., Tatsumoto, N., Fujii, K., Ohmori, H., and Kuniyasu, H., Suppression of dendritic cells by HMGB1 is associated with lymph node metastasis of human colon cancer, Pathobiology, 2009, vol. 76, no. 4, pp. 155–162.

    Article  PubMed  CAS  Google Scholar 

  77. Ladoire, S., Arnould, L., Mignot, G., Apetoh, L., Rébé, C., Martin, F., Coudert, B., and Ghiringhelli, F., T-bet expression in intratumoral lymphoid structures after neoadjuvant trastuzumab plus docetaxel for HER2-overexpressing breast carcinoma predicts survival, Br. J. Cancer, 2011a, vol. 105, no. 3, pp. 366–371.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Ladoire, S., Mignot, G., Dabakuyo, S., Arnould, L., Ap-etoh, L., Rébé, C., Coudert, B., Martin, F., Bizollon, M.H., Vanoli, A., Coutant, C., Fumoleau, P., Bonnetain, F., and Ghiringhelli, F., In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival, J. Pathol., 2011b, vol. 224, no. 3, pp. 389–400.

    Article  PubMed  CAS  Google Scholar 

  79. Laoui, D., Overmeire van, E., and Ginderachter van, J.A., Unsuspected allies: chemotherapy teams up with immunity to fight cancer, Eur. J. Immunol., 2013, vol. 43, no. 10, pp. 2538–2542.

    Article  PubMed  CAS  Google Scholar 

  80. Liu, C.Y., Xu, J.Y., Shi, X.Y., Huang, W., Ruan, T.Y., Xie, P., and Ding, J.L., M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway, Lab. Invest., 2013, vol. 93, no. 7, pp. 844–854.

    Article  PubMed  CAS  Google Scholar 

  81. Liu, H., Zhang, T., Ye, J., Li, H., Huang, J., Li, X., Wu, B., Huang, X., and Hou, J., Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer, Cancer Immunol., Immunother., 2012, vol. 61, no. 10, pp. 1849–1856.

    Article  CAS  Google Scholar 

  82. Loi, S., Sirtaine, N., Piette, F., Salgado, R., Viale, G., van Eenoo, F., Rouas, G., Francis, P., Crown, J.P., Hitre, E., de Azambuja, E., Quinaux, E., Di Leo, A., Michiels, S., Piccart, M.J., and Sotiriou, C., Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02–98, J. Clin. Oncol., 2013, vol. 31, no. 7, pp. 860–867.

    Article  PubMed  CAS  Google Scholar 

  83. Lu, N., Wang, L., Cao, H., Liu, L., van Kaer L., Washington, M.K., Rosen, M.J., Dube, P.E., Wilson, K.T., Ren, X., and Yan, F., Activation of the epidermal growth factor receptor in macrophages regulates cytokine production and experimental colitis, J. Immunol., 2014, vol. 192, no. 3, pp. 1013–1023.

    Article  PubMed  CAS  Google Scholar 

  84. Lu, L., Pan, K., Li, X.D., She, K.L., Zhao, J.J., Wang, W., Chen, J.G., Chen, Y.B., Yun, J.P., and Xia, J.C., The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma, PLoS One, 2011, vol. 6, no. 3, p. e18219.

    Article  CAS  Google Scholar 

  85. Ma, Y., Shurin, G.V., Gutkin, D.W., and Shurin, M.R., Tumor associated regulatory dendritic cells, Semin. Cancer Biol., 2012, vol. 22, no. 4, pp. 298–306.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Martinez, F.O. and Gordon, S., The M1 and M2 paradigm of macrophage activation: time for reassessment, F1000Prime Rep., 2014, vol. 6, p. 13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Matise, L.A., Palmer, T.D., Ashby, W.J., Nashabi, A., Chytil, A., Aakre, M., Pickup, M.W., Gorska, A.E., Zijlstra, A., and Moses, H.L., Lack of transforming growth factor-β signaling promotes collective cancer cell invasion through tumor-stromal crosstalk, Breast Cancer Res., 2012, vol. 14, no. 4, p. R98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Mattarollo, S.R., Loi, S., Duret, H., Ma, Y., Zitvogel, L., and Smyth, M.J., Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors, Cancer Res., 2011, vol. 71, no. 14, pp. 4809–4820.

    Article  PubMed  CAS  Google Scholar 

  89. McGee, H.M., Schmidt, B.A., Booth, C.J., Yancopou-los, G.D., Valenzuela, D.M., Murphy, A.J., Stevens, S., Flavell, R.A., and Horsley, V., IL-22 promotes fibroblast-mediated wound repair in the skin, J. Invest. Dermatol., 2013, vol. 133, no. 5, pp. 1321–1329.

    Article  PubMed  CAS  Google Scholar 

  90. Milani, A., Sangiolo, D., Aglietta, M., and Valabrega, G., Recent advances in the development of breast cancer vaccines, Breast Cancer, 2014, vol. 6, pp. 159–168.

    PubMed  CAS  PubMed Central  Google Scholar 

  91. Miyara, M., Yoshioka, Y., Kitoh, A., Shima, T., Wing, K., Niwa, A., Parizot, C., Taflin, C., Heike, T., Valeyre, D., Mathian, A., Nakahata, T., Yamaguchi, T., Nomura, T., Ono, M., et al., Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor, Immunity, 2009, vol. 30, no. 6, pp. 899–911.

    Article  PubMed  CAS  Google Scholar 

  92. Motz, G.T. and Coukos, G., The parallel lives of angiogenesis and immunosuppression: cancer and other tales, Nat. Rev. Immunol., 2011, vol. 11, no. 10, pp. 702–711.

    Article  PubMed  CAS  Google Scholar 

  93. Motz, G.T., Santoro, S.P., Wang, L.P., Garrabrant, T., Lastra, R.R., Hagemann, I.S., Lal, P., Feldman, M.D., Benencia, F., and Coukos, G., Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors, Nat. Med., 2014, vol. 20, no. 6, pp. 607–615.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Mueller, M.M. and Fusenig, N.E., Friends or foes—bipolar effects of the tumour stroma in cancer, Nat. Rev. Cancer, 2004, vol. 4, no. 11, pp. 839–849.

    Article  PubMed  CAS  Google Scholar 

  95. Murphy, K.M. and Reiner, S.L., The lineage decisions of helper T cells, Nat. Rev. Immunol., 2002, vol. 2, no. 12, pp. 933–944.

    Article  PubMed  CAS  Google Scholar 

  96. Murphy, T.J., Ni Choileain, N., Zang, Y., Mannick, J.A., and Lederer, J.A. CD4+CD25+ regulatory T cells control innate immune reactivity after injury, J. Immunol., 2005, vol. 174, no. 5, pp. 2957–2963.

    Article  PubMed  CAS  Google Scholar 

  97. Müschen, M., Moers, C., Warskulat, U., Even, J., Niederacher, D., and Beckmann, M.W., CD95 ligand expression as a mechanism of immune escape in breast cancer, Immunology, 2000, vol. 99, no. 1, pp. 69–77.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Neill, D.R., Wong, S.H., Bellosi, A., Flynn, R.J., Daly, M., Langford, T.K., Bucks, C., Kane, C.M., Fallon, P.G., Pannell, R., Jolin, H.E., and McKenzie, A.N., Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity, Nature, 2010, vol. 464, no. 7293, pp. 1367–1370.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Nielsen, J.S., Sahota, R.A., Milne, K., Kost, S.E., Nesslinger, N.J., Watson, P.H., and Nelson, B.H., CD20+ tumor-infiltrating lymphocytes have an atypical CD27– memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer, Clin. Cancer Res., 2012, vol. 18, no. 12, pp. 3281–3292.

    Article  PubMed  CAS  Google Scholar 

  100. Numasaki, M., Fukushi, J., Ono, M., Narula, S.K., Zavodny, P.J., Kudo, T., Robbins, P.D., Tahara, H., and Lotze, M.T., Interleukin-17 promotes angiogenesis and tumor growth, Blood, 2003, vol. 101, no. 7, pp. 2620–2627.

    Article  PubMed  CAS  Google Scholar 

  101. Paget, S., The distribution of secondary growths in cancer of the breast. 1889, Cancer Metastasis Rev., 1989, vol. 8, no. 2, pp. 98–101.

    PubMed  CAS  Google Scholar 

  102. Paris, I., Charreau, S., Guignouard, E., Garnier, M., Favot-Laforge, L., Huguier, V., Bernard, F.-X., Morel, F., and Lecron, J.-C., Critical role of Th17 pro-inflammatory cytokines to delay skin wound healing, Cytokine, 2012, vol. 59, no. 3, p. 503.

    Article  Google Scholar 

  103. Peng, G., Guo, Z., Kiniwa, Y., Voo, K.S., Peng, W., Fu, T., Wang, D.Y., Li, Y., Wang, H.Y., and Wang, R.F., Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function, Science, 2005, vol. 309, no. 5739, pp. 1380–1384.

    Article  PubMed  CAS  Google Scholar 

  104. Perelmuter, V.M. and Manskikh, V.N., Preniche as missing link of the metastatic niche concept explaining organ-preferential metastasis of malignant tumors and the type of metastatic disease, Biochemistry (Moscow), 2012, vol. 77, no. 1, pp. 111–118.

    PubMed  CAS  Google Scholar 

  105. Perelmuter, V.M., Slonimskaya, E.M., Cherdyntseva, N.V., and Afrimzon, E.A., Prognostic significance of immunocompetent cell infiltration of breast tumor tissue, Vopr. Onkol., 1997, vol. 43, no. 6, pp. 596–598.

    CAS  Google Scholar 

  106. Perelmuter, V.M., Vtorushin, S.V., Odintsov, Yu.N., Zavyalova, M.V., Slonimskaya, E.M., and Savenkova, O.V., Inflammatory infiltration in stroma of invasive ductal breast carcinoma in development of recurrence, Sib. Onkol. Zh., 2010, no. 5, pp. 11–16.

  107. Rak, G.D., Osborne, L.C., Siracusa, M.C., Kim, B.S., Wang, K., Bayat, A., Artis, D., and Volk, S.W., IL-33-dependent Group 2 innate lymphoid cells promote cutaneous Wound Healing, J. Invest. Dermatol., 2016, vol. 136, no. 2, pp. 487–496.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Rollins, B.J., Inflammatory chemokines in cancer growth and progression, Eur. J. Cancer, 2006, vol. 42, no. 6, pp. 760–767.

    Article  PubMed  CAS  Google Scholar 

  109. Ruffell, B., Au, A., Rugo, H.S., Esserman, L.J., Hwang, E.S., and Coussens, L.M., Leukocyte composition of human breast cancer, Proc. Natl. Acad. Sci. U.S.A., 2012, vol. 109, no. 8, pp. 2796–2801.

    Article  PubMed  Google Scholar 

  110. Sabatier, R., Finetti, P., Mamessier, E., Raynaud, S., Cervera, N., Lambaudie, E., Jacquemier, J., Viens, P., Birnbaum, D., and Bertucci, F., Kinome expression profiling and prognosis of basal breast cancers, Mol. Cancer, 2011, vol. 10, p. 86.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Salgado, R., Denkert, C., Campbell, C., Savas, P., Nuciforo, P., Nucifero, P., Aura, C., de Azambuja, E., Eidtmann, H., Ellis, C.E., Baselga, J., Piccart-Gebhart, M.J., Michiels, S., Bradbury, I., Sotiriou, C., and Loi, S., Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial, J.A.M.A. Oncol., 2015a, vol. 1, no. 4, pp. 448–454.

    Google Scholar 

  112. Salgado, R., Denkert, C., Demaria, S., Sirtaine, N., Klauschen, F., et al., The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014, Ann. Oncol., 2015b, vol. 26, no. 2, pp. 259–271.

    Article  PubMed  CAS  Google Scholar 

  113. Savas, P., Salgado, R., Denkert, C., Sotiriou, C., Darcy, P.K., Smyth, M.J., and Loi, S., Clinical relevance of host immunity in breast cancer: from TILs to the clinic, Nat. Rev. Clin. Oncol., 2016, vol. 13, no. 4, pp. 228–241.

    Article  PubMed  CAS  Google Scholar 

  114. Scapini, P., Lapinet-Vera, J.A., Gasperini, S., Calzetti, F., Bazzoni, F., and Cassatella, M.A., The neutrophil as a cellular source of chemokines, Immunol. Rev., 2000, vol. 177, pp. 195–203.

    Article  PubMed  CAS  Google Scholar 

  115. Schnyder-Candrian, S., Togbé, D., Couillin, I., Mercier, I., Brombacher, F., Quesniaux, V., Fossiez, F., Ryffel, B., and Schnyder, B., Interleukin-17 is a negative regulator of established allergic asthma, J. Exp. Med., 2006, vol. 203, no. 12, pp. 2715–2725.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Sharma, P., Retz, M., Siefker-Radtke, A., Baron, A., Necchi, A., et al., Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial, Lancet Oncol., 2017, vol. 18, no. 3, pp. 312–322.

    Article  PubMed  CAS  Google Scholar 

  117. Shen, M., Hu, P., Donskov, F., Wang, G., Liu, Q., and Du, J., Tumor-associated neutrophils as a new prognostic factor in cancer: a systematic review and meta-analysis, PLoS One, 2014, vol. 9, no. 6, p. e98259.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Shintani, Y., Fujiwara, A., Kimura, T., Kawamura, T., Funaki, S., Minami, M., and Okumura, M., IL-6 secreted from cancer-associated fibroblasts mediates chemo-resistance in NSCLC by increasing epithelial-mesenchymal transition signaling, J. Thorac. Oncol., 2016, vol. 11, no. 9, pp. 1482–1492.

    Article  PubMed  Google Scholar 

  119. Shipp, C., Speigl, L., Janssen, N., Martens, A., and Pawelec, G., A clinical and biological perspective of human myeloid-derived suppressor cells in cancer, Cell Mol. Life Sci., 2016, vol. 73, no. 21, pp. 4043–4061.

    Article  PubMed  CAS  Google Scholar 

  120. Shurin, M.R. and Lotze, M.T., Dendritic cells in cancer: emergence of the discipline, in Dendritic Cells in Cancer, New York: Springer-Verlag, 2009, pp. 11–30.

    Google Scholar 

  121. Sica, A. and Mantovani, A., Macrophage plasticity and polarization: in vivo veritas, J. Clin. Invest., 2012, vol. 122, no. 3, pp. 787–795.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Sindrilaru, A., Peters, T., Wieschalka, S., Baican, C., Baican, A., Peter, H., Hainzl, A., Schatz, S., Qi, Y., Schlecht, A., Weiss, J.M., Wlaschek, M., Sunderkötter, C., and Scharffetter-Kochanek, K., An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice, J. Clin. Invest., 2011, vol. 121, no. 3, pp. 985–997.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Spaderna, S., Schmalhofer, O., Hlubek, F., Berx, G., Eger, A., Merkel, S., Jung, A., Kirchner, T., and Brabletz, T., A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer, Gastroenterology, 2006, vol. 131, no. 3, pp. 830–840.

    Article  PubMed  CAS  Google Scholar 

  124. Sullivan, N.J., Sasser, A.K., Axel, A.E., Vesuna, F., Raman, V., Ramirez, N., Oberyszyn, T.M., and Hall, B.M., Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells, Oncogene, 2009, vol. 28, no. 33, pp. 2940–2947.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Tashireva, L.A., Zavyalova, M.V., Savelieva, O.E., Vtorushin, S.V., Kaigorodov, E.V., Denisov, E.V., Slonimskaya, E.M., and Perelmuter, V.M., Heterogenic distribution of cytotoxic T-lymphosytes in the stroma of invasive breast carcinoma: prognostic significance, Mezhd. Zh. Prikl. Fundam. Issled., 2015, no. 7-1, pp. 73–75.

  126. Tashireva, L.A., Perelmuter, V.M., Manskikh, V.N., Denisov, E.V., Savelieva, O.E., Kaygorodova, E.V., and Zavyalova, M.V., Types of immune-inflammatory responses as a reflection of cell–cell interactions under conditions of tissue regeneration and tumor growth, Biochemistry (Moscow), 2017a, vol. 82, no. 5, pp. 542–555.

    PubMed  CAS  Google Scholar 

  127. Tashireva, L.A., Denisov, E.V., Gerashchenko, T.S., Pautova, D.N., Buldakov, M.A., Zavyalova, M.V., Kzhyshkowska, J., Cherdyntseva, N.V., and Perelmuter, V.M., Intratumoral heterogeneity of macrophages and fibroblasts in breast cancer is associated with the morphological diversity of tumor cells and contributes to lymph node metastasis, Immunobiology, 2017b, vol. 222, no. 4, pp. 631–640.

    Article  PubMed  CAS  Google Scholar 

  128. Thiery, J.P., Epithelial-mesenchymal transitions in tumour progression, Nat. Rev. Cancer, 2002, vol. 2, no. 6, pp. 442–454.

    Article  PubMed  CAS  Google Scholar 

  129. Treilleux, I., Blay, J.Y., Bendriss-Vermare, N., Ray-Coquard, I., Bachelot, T., Guastalla, J.P., Bremond, A., Goddard, S., Pin, J.J., Barthelemy-Dubois, C., and Lebecque, S., Dendritic cell infiltration and prognosis of early stage breast cancer, Clin. Cancer Res., 2004, vol. 10, no. 22, pp. 7466–7474.

    Article  PubMed  CAS  Google Scholar 

  130. Twomey, J.D., Brahme, N.N., and Zhang, B., Drug-biomarker co-development in oncology—20 years and counting, Drug Resist. Updates, 2017, vol. 30, pp. 48–62.

    Article  Google Scholar 

  131. Watkins, S.K., Egilmez, N.K., Suttles, J., and Stout, R.D., IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo, J. Immunol., 2007, vol. 178, no. 3, pp. 1357–1362.

    Article  PubMed  CAS  Google Scholar 

  132. West, N.R., Milne, K., Truong, P.T., Macpherson, N., Nelson, B.H., and Watson, P.H., Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer, Breast Cancer Res., 2011, vol. 13, no. 6, p. R126.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Wieder, T., Braumüller, H., Kneilling, M., Pichler, B., and Röcken, M., T cell-mediated help against tumors, Cell Cycle, 2008, vol. 7, no. 19, pp. 2974–2977.

    Article  PubMed  CAS  Google Scholar 

  134. Wolf, A.M., Wolf, D., Steurer, M., Gastl, G., Gunsilius, E., and Grubeck-Loebenstein, B., Increase of regulatory T cells in the peripheral blood of cancer patients, Clin. Cancer Res., 2003, vol. 9, no. 2, pp. 606–612.

    PubMed  Google Scholar 

  135. Wynn, T.A., Cellular and molecular mechanisms of fibrosis, J. Pathol., 2008, vol. 214, no. 2, pp. 199–210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Yang, X.O., Nurieva, R., Martinez, G.J., Kang, H.S., Chung, Y., Pappu, B.P., Shah, B., Chang, S.H., Schluns, K.S., Watowich, S.S., Feng, X.H., Jetten, A.M., and Dong, C., Molecular antagonism and plasticity of regulatory and inflammatory T cell programs, Immunity, 2008, vol. 29, no. 1, pp. 44–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Yang, Y., Huang, C.T., Huang, X., and Pardoll, D.M., Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance, Nat. Immunol., 2004, vol. 5, no. 5, pp. 508–515.

    Article  PubMed  CAS  Google Scholar 

  138. Zavyalova, M.V., Perelmuter, V.M., Slonimskaya, E.M., Vtorushin, S.V., Garbukov, E.Yu., and Glushchenko, S.A., Relation between lymphogenous metastasis and the histological structure of the infiltrative component of ductal breast carcinoma, Sib. Onkol. Zh., 2006, no. 1, pp. 32–35.

  139. Zavyalova, M.V., Perelmuter, V.M., Vtorushin, S.V., Denisov, E.V., Litvyakov, N.V., Slonimskaya, E.M., and Cherdyntseva, N.V., The presence of alveolar structures in invasive ductal NOS breast carcinoma is associated with lymph node metastasis, Diagn. Cytopathol., 2013, vol. 41, no. 3, pp. 279–282.

    Article  PubMed  Google Scholar 

  140. Zeisberg, M. and Neilson, E.G., Biomarkers for epithelialmesenchymal transitions, J. Clin. Invest., 2009, vol. 119, no. 6, pp. 1429–1437.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Zhang, Q., Jia, Q., Deng, T., Song, B., and Li, L., Heterogeneous expansion of CD4+ tumor-infiltrating T-lymphocytes in clear cell renal cell carcinomas, Biochem. Biophys. Res. Commun., 2015, vol. 458, no. 1, pp. 70–76.

    Article  PubMed  CAS  Google Scholar 

  142. Zhang, Y., Gu, W., He, L., and Sun, B., Th1/Th2 cell’s function in immune system, Adv. Exp. Med. Biol., 2014, vol. 841, pp. 45–65.

    Article  PubMed  CAS  Google Scholar 

  143. Zheng, X.F., Hong, Y.X., Feng, G.J., Zhang, G.F., Rogers, H., Lewis, M.A., Williams, D.W., Xia, Z.F., Song, B., and Wei, X.Q., Lipopolysaccharide-induced M2 to M1 macrophage transformation for IL-12p70 production is blocked by Candida albicans mediated up-regulation of EBI3 expression, PLoS One, 2013, vol. 8, no. 5, p. e63967.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Zhou, S., Jin, X., Li, Y., Li, W., Chen, X., Xu, L., Zhu, J., Xu, Z., Zhang, Y., Liu, F., and Su, C., Blockade of PD-1 signaling enhances Th2 cell responses and aggravates liver immunopathology in mice with Schistosomiasis japonica, PLoS Negl. Trop. Dis., 2016, vol. 10, no. 10, p. e0005094.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Zhou, X., Bailey-Bucktrout, S.L., Jeker, L.T., Penaranda, C., Martínez-Llordella, M., Ashby, M., Nakayama, M., Rosenthal, W., and Bluestone, J.A., Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo, Nat. Immunol., 2009, vol. 10, no. 9, pp. 1000–1007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Zhu, J. and Paul, W.E., Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors, Immunol. Rev., 2010, vol. 238, no. 1, pp. 247–262.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Zhu, J., Guo, L., Min, B., Watson, C.J., Hu-Li, J., Young, H.A., Tsichlis, P.N., and Paul, W.E., Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation, Immunity, 2002, vol. 16, no. 5, pp. 733–744.

    Article  PubMed  CAS  Google Scholar 

  148. Zhu, J., Davidson, T.S., Wei, G., Jankovic, D., Cui, K., Schones, D.E., Guo, L., Zhao, K., Shevach, E.M., and Paul, W.E., Down-regulation of Gfi-1 expression by TGF-β is important for differentiation of Th17 and CD103+ inducible regulatory T cells, J. Exp. Med., 2009, vol. 206, no. 2, pp. 329–341.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Zijl van, F., Krupitza, G., and Mikulits, W., Initial steps of metastasis: cell invasion and endothelial transmigration, Mutat. Res., 2011, vol. 728, nos. 1–2, pp. 23–34.

Download references

ACKNOWLEDGMENTS

This work was supported by the Russian Science Foundation (project no. 16-15-10221).

COMPLIANCE WITH ETHICAL STANDARDS

Сonflict of interests. The authors declare that they have no conflict of interest.

Statement on the welfare of animals This article does not contain any studies with human participants or animals performed by any of the authors. .

Informed Consent. For this type of study informed consent is not required.

Author information

Authors and Affiliations

  1. Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050, Tomsk, Russia

    V. M. Perelmuter, L. A. Tashireva, E. V. Denisov, O. E. Savelieva, E. V. Kaygorodova & M. V. Zavyalova

  2. Department of Bioengineering and Bioinformatics, Moscow State University, 119991, Moscow, Russia

    V. N. Manskikh

  3. Tomsk State University, 634050, Tomsk, Russia

    E. V. Denisov, O. E. Savelieva & M. V. Zavyalova

  4. Siberian State Medical University, 634050, Tomsk, Russia

    M. V. Zavyalova

Authors
  1. V. M. Perelmuter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. A. Tashireva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. N. Manskikh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. V. Denisov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O. E. Savelieva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. V. Kaygorodova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. V. Zavyalova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. V. Denisov.

Additional information

Translated by T. Tkacheva

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Perelmuter, V.M., Tashireva, L.A., Manskikh, V.N. et al. Heterogeneity and Plasticity of Immune Inflammatory Responses in the Tumor Microenvironment: Their Role in the Antitumor Effect and Tumor Aggressiveness. Biol Bull Rev 8, 431–448 (2018). https://doi.org/10.1134/S2079086418050055

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S2079086418050055

Keywords

Search

Navigation