Visoke vrednosti CD14+B7H4+ populacije monocita su značajno povezane sa povišenim koncentracijama IL-4, IL-13, IL-10 i TGF-β1 u tumorskoj mikrocirkulaciji karcinoma pluća
Sažetak
Uvod/Cilj. Karcinom pluća (KP) je jedan od vodećih uzroka smrtnosti. Napredovanje bolesti i uznapredovala bolest karakterišu se neprotektivnim imunološkim odgovorom zbog polarizacije M2 makrofaga, aktivnosti supresorskih ćelija mijeloidnog porekla (MDSC), neravnoteže citokina i regulatorne aktivnosti T limfocita. Cilj rada bio je da se utvrdi povezanost između Th1/Th2 citokina i CD14+B7H4+ broja monocita (Mo) kod bolesnika sa KP. Metode. Ispitali smo glavne Th1/Th2 citokine i broj CD14+B7H4+ Mo u uzorcima iz krvi i mikrocirkulacije tumora 41 bolesnika sa KP (III i IV klinički stadijum) i 30 zdravih ispitanika (kontrolna grupa). Rezultati. Koncentracija ispitivanih citokina u serumu bolesnika u odnosu na zdrave ispitanike nije se značajno razlikovala. Stratifikacija u histološkim grupama tumora, obimu bolesti i veličini tumora otkrila je značajne razlike. Kod bolesnika sa KP različitih histoloških tipova utvrđene su značajne razlike, kako u uzorcima seruma tako i u mikrocirkulaciji tumora. Prisustvo metastaza bilo je povezano sa povećanjem IFN-γ/IL-4 u krvi i povećanjem IL-13 u uzorcima mikrocirkulacije tumora. Uzorci
mikrocirkulacije najvećih tumora okarakterisani su Th2 citokinskim profilom. Ispitivanje CD14+B7H4+ Mo u uzorcima krvi pokazalo je značajnu povezanost ekstremne vrednosti te ćelijske populacije sa povišenim udelom IL-2/IL-13. Bolesnici sa najvećim brojem CD14+B7H4+ Mo u uzorcima mikrocirkulacije tumora pokazali su značajan porast IL-4, IL-13, IL-10 i TGF-β1. Zaključak. Bolesnici sa KP pokazuju polarizaciju citokinskog odgovora povezanu sa vrstom mikrookoline, histološkim tipom tumora, veličinom tumora i proširenošću bolesti. Najveće vrednosti broja CD14+B7H4+ monocita značajno su povezane sa Th2 citokinskim profilom.
Reference
Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 2011; 32(4): 605−44.
Travis WD, Brambilla E, Riely GJ. New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J Clin Oncol 2013; 31(8): 992−1001.
Chen J, Sun W, Zhang H, Ma J, Xu P, Yu Y, et al. Macrophages reprogrammed by lung cancer microparticles promote tumor development via release of IL-1β. Cell Mol Immunol 2019; doi: 10.1038/s41423-019-0313-2. (In Press)
Ma J, Xu H, Wang S. Immunosuppressive Role of Myeloid-Derived Suppressor Cells and Therapeutic Targeting in Lung Cancer. J Immunol Res 2018; 2018: 6319649.
Barrera L, Montes-Servín E, Barrera A, Ramírez-Tirado LA, Salinas-Parra F, Bañales-Méndez JL, et al. Cytokine profile determined by data-mining analysis set into clusters of non-small-cell lung cancer patients according to prognosis. Ann Oncol 2015; 26(2): 428−35.
Marrugal Á, Ojeda L, Paz-Ares L, Molina-Pinelo S, Ferrer I. Proteomic-Based Approaches f or the Study of Cytokines in Lung Cancer. Dis Markers 2016; 2016: 2138627.
Liu C, Wu S, Meng X, Liu G, Chen D, Cong Y, et al. Predictive Value of Peripheral Regulatory T Cells in Non-Small Cell Lung Cancer Patients Undergoing Radiotherapy. Oncotarget 2017; 8(26): 43427−38.
Asselin-Paturel C, Echchakir H, Carayol G, Gay F, Opolon P, Grunenwald D, et al. Quantitative analysis of Th1, Th2 and TGF-beta1 cytokine expression in tumor, TIL and PBL of non-small cell lung cancer patients. Int J Cancer 1998; 77(1): 7−12.
Wei H, Sun R, Xiao W, Feng J, Zhen C, Xu X, et al. Type Two Cytokines Predominance of Human Lung Cancer and Its Reverse by Traditional Chinese Medicine TTMP. Cell Mol Immunol 2004; 1(1): 63−70.
Ma J, Liu H, Wang X. Effect of ginseng polysaccharides and dendritic cells on the balance of Th1/Th2 T helper cells in patients with non-small cell lung cancer. J Tradit Chin Med 2014; 34(6): 641−5.
Li J, Wang Z, Mao K, Guo X. Clinical significance of serum T helper 1/T helper 2 cytokine shift in patients with nonsmall cell lung cancer. Oncol Lett 2014; 8(4): 1682−6.
Chen YC, Hsiao CC, Chen KD, Hung YC, Wu CY, Lie CH, et al. Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy. PLoS ONE 2013; 8(2): e57053.
Ghayumi MA, Mojtahedi Z, Fattahi MJ. Th1 and Th2 Cytokine Profiles in Malignant Pleural Effusion. Iran J Immunol 2011; 8(4): 195−200.
Li R, Ruttinger D, Li R, Si LS, Wang YL. Analysis of the immunological microenvironment at the tumor site in patients with non-small cell lung cancer. Langenbecks Arch Surg 2003; 388(6): 406–12.
Zhang B, Yao G, Zhang Y, Gao J, Yang B, Rao Z, et al. M2-Polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymph angiogenesis in lung adenocarcinoma. Clinics 2011; 66(11): 1879−86.
Hodge G, Barnawi J, Jurisevic C, Moffat D, Holmes M, Reynolds PN, et al. Lung cancer is associated with decreased expression of perforin, granzyme B and interferon (IFN)-γ by infiltrating lung tissue T cells, natural killer (NK) T-like and NK cells. Clin Exp Immunol 2014; 178(1): 79−85.
Chang CH, Hsiao CF, Yeh YM, Chang GC, Tsai YH, Chen YM, et al. Circulating interleukin-6 level is a prognostic marker for survival in advanced non-small cell lung cancer patients treated with chemotherapy. Int J Cancer 2013; 132(9): 1977−85.
Zilionis R, Engblom C, Pfirschke C, Savova V, Zemmour D, Saatcioglu HD, et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 2019; 50(5): 1317−34.e10.
Zhang S, Che D, Yang F, Chi C, Meng H, Shen J, et al. Tumor-associated macrophages promote tumor metastasis via the TGF-beta/SOX9 axis in non-small cell lung cancer. Oncotarget 2017; 8(59): 99801−15.
Wang R, Zhang J, Chen S, Lu M, Luo X, Yao S, et al. Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression. Lung Cancer 2011; 74(2): 188−96.
Pogoda K, Pyszniak M, Rybojad P, Tabarkiewicz J. Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer. Oncol Lett 2016; 12(6): 4785−94.
Vuković J, Karlicic, Ristić S, Stanojević , Nikolic N, Stefik D, et al. Significance of MDSC alike CD14+B7H4+ cells frequency in blood and tumor microcirculation of lung cancer patients. Vojnosanit Pregl 2019; doi: 10.2298/VSP190430106V (In Press)
Ito N, Nakamura H, Metsugi H, Ohgi S. Dissociation between T helper type 1 / type 2 differentiation and cytokine production of tumor-infiltrating lymphocytes in lung cancer patients. Surg Today 2001; 31(5): 390−4.
Ito N, Suzuki Y, Taniguchi Y, Ishiguro K, Nakamura H, Ohgi S. Prognostic significance of T helper 1 and 2 and T cytotoxic 1 and 2 cells in patients with non-small cell lung cancer. Anticancer Res 2005; 25(3B): 2027−31.
Fritz JM, Dwyer-Nield LD, Malkinson AM. Stimulation of neoplastic mouse lung cell proliferation by alveolar macrophage-derived, insulin-like growth factor-1 can be blocked by inhibiting MEK and PI3K activation. Mol Cancer 2011; 10: 76.
Gocheva V, Wang HW, Gadea BB, Shree T, Hunter KE, Garfall AL, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 2010; 24(3): 241−55.
Feng PH, Lee KY, Chang YL, Chan YF, Kuo LW, Lin TY, et al. CD14+S100A9+ Monocytic Myeloid-derived Suppressor Cells and Their Clinical Relevance in Non–Small Cell Lung Cancer. Am J Respir Crit Care Med 2012; 186(10): 1025−36.
Huang M, Wang J, Lee P, Stiantila S, Mao JT, Meissner H, et al. Human Non-Small Cell Lung Cancer Cells Express a Type 2 Cytokine Pattern. Cancer Res 1995; 55(17): 3847−53.
Fujisawa T, Joshi BH, Puri RK. IL-13 regulates cancer invasion and metastasis through IL-13Rα2 via ERK/AP-1 pathway in mouse model of human ovarian cancer. Int J Cancer 2012; 131(2): 344−56.
Fujisawa T, Joshi B, Nakajima A, Puri RK. A Novel Role of Interleukin-13 Receptor α2 in Pancreatic Cancer Invasion and Metastasis. Cancer Res 2009; 69(22): 8678–85.