Abstract
There are significant differences in pathology, etiology, clinical features, and treatment options between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). However, the differences of macrophage distribution and its associated function between SCLC and NSCLC are not fully investigated. Through methods of flow cytometry and cytometric bead array, we examined the levels of various subtypes of macrophages, monocytes, and regulatory T cells (Tregs) as well as interleukin (IL)-10 in bronchoalveolar lavage fluid (BALF) of patients with SCLC or NSCLC. Our study showed that the frequency of CD14+, CD206+CD14+ and IL-10+CD206+CD14+M2-like macrophages were significantly increased, with simultaneously elevated IL-10 in BALF of SCLC patients, as compared to those in BALF of NSCLC patients. Furthermore, the increased frequency of IL-10+CD206+CD14+M2-like macrophages and elevated level of IL-10 in BALF of SCLC patients were positively correlated with advanced tumor stage, but negatively correlated with their survival time. On the other hand, the level of supernatant IL-10 and frequency of IL-10+CD206+CD14+M2-like macrophages in SCLC patients were positively correlated. The frequency of above mentioned macrophages was also positively correlated with that of Foxp3+CD25+CD4+Tregs. Compared to NSCLC patients, the level of circulating IL-10+CD206+CD14+M2-like monocytes in SCLC patients were significantly increased after chemotherapy. Overall, increased IL-10+CD206+CD14+M2-like macrophages were an important feature of SCLC, rather than NSCLC, and it is associated with development of SCLC.
Similar content being viewed by others
References
Haddadin S, Perry MC (2011) History of small-cell lung cancer. Clin Lung Cancer 12(2):87–93
Murray N, Turrisi AR (2006) A review of first-line treatment for small-cell lung cancer. J Thoraconcol 1(3):270–278
Kurahara Y, Kawaguchi T, Tachibana K, Atagi S, Hayashi S, Kitaichi M, Ou SH, Takada M (2012) Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke. Clin Lung Cancer 13(1):75–79
Urman A, DeanHosgood H (2015) Lung cancer risk, genetic variation, and air pollution. EBioMedicine 2(6):491–492
Houghton AM (2013) Mechanistic links between COPD and lung cancer. Nat Rev Cancer 13(4):233–245
Ren F, Fan M, Mei J, Wu Y, Liu C, Pu Q, You Z, Liu L (2014) Interferon-γ and celecoxib inhibit lung-tumor growth through modulating M2/M1 macrophage ratio in the tumor microenvironment. Drug Des Dev Ther 8:1527–1538
Chung FT, Lee KY, Wang CW, Heh CC, Chan YF, Chen HW, Kuo CH, Feng PH, Lin TY, Wang CH, Chou CL, Chen HC, Lin SM, Kuo HP (2012) Tumor-associated macrophages correlate with response to epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small cell lung cancer. Int J Cancer 131(3):E227–E235
Savai R, Schermuly RT, Pullamsetti SS, Schneider M, Greschus S, Ghofrani HA, Traupe H, Grimminger F, Banat GA (2007) A combination hybrid-based vaccination/adoptive cellular therapy to prevent tumor growth by involvement of T cells. Cancer Res 67(11):5443–5453
Uo M, Hisamatsu T, Miyoshi J, Kaito D, Yoneno K, Kitazume MT, Mori M, Sugita A, Koganei K, Matsuoka K, Kanai T, Hibi T (2013) Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14 macrophage activation. Gut 62(12):1734–1744
Heeren AM, Kenter GG, Jordanova ES, de Gruijl TD (2015) CD14+ macrophage-like cells as the linchpin of cervical cancer perpetrated immune suppression and early metastatic spread. A new therapeutic lead? Oncoimmunology 4(6):e1009296
Yuan A, Hsiao YJ, Chen HY, Chen HW, Ho CC, Chen YY, Liu YC, Hong TH, Yu SL, Chen JJ, Yang PC (2015) Opposite effects of M1 and M2 macrophage subtypes on lung cancer progression. Sci Rep 5:14273
Smith PD, Smythies LE, Shen R, Greenwell-Wild T, Gliozzi M, Wahl SM (2011) Intestinal macrophages and response to microbial encroachment. Mucosal Immunol 4(1):31–42
Martinez F, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. https://doi.org/10.12703/P6-13
Medeiros LT, Peraçoli JC, Bannwart-Castro CF, Romão M, Weel IC, Golim MA, de Oliveira LG, Kurokawa CS, Medeiros Borges VT, Peraçoli MT (2014) Monocytes from pregnant women with pre-eclampsia are polarized to a M1 phenotype. Am J Reprod Immunol 72(1):5–13
Almatroodi SA, McDonald CF, Darby IA, Pouniotis DS (2016) Characterization of M1/M2 tumour-associated macrophages (TAMs) and Th1/Th2 cytokine profiles in patients with NSCLC. Cancer Microenviron 9(1):1–11
Ma J, Liu L, Che G, Yu N, Dai F, You Z (2010) The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer. https://doi.org/10.1186/1471-2407-10-112
Iriki T, Ohnishi K, Fujiwara Y, Horlad H, Saito Y, Pan C, Ikeda K, Mori T, Suzuki M, Ichiyasu H, Kohrogi H, Takeya M, Komohara Y (2017) The cell–cell interaction between tumor-associated macrophages and small cell lung cancer cells is involved in tumor progression via STAT3 activation. Lung Cancer 106:22–32
Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51
Redente EF, Dwyer-Nield LD, Merrick DT, Raina K, Agarwal R, Pao W, Rice PL, Shroyer KR, Malkinson AM (2010) Tumor progression stage and anatomical site regulate tumor-associated macrophage and bone marrow-derived monocyte polarization. Am J Pathol 176(6):2972–2985
Hsu TI, Wang YC, Hung CY, Yu CH, Su WC, Chang WC, Hung JJ (2016) Positive feedback regulation between IL-10 and EGFR promotes lung cancer formation. Oncotarget 7(15):20840–20854
Zhu Q, Wu X, Wu Y, Wang X (2016) Interaction between Treg cells and tumor-associated macrophages in the tumor microenvironment of epithelial ovarian cancer. Oncol Rep 36(6):3472–3478
Tcyganov E, Mastio J, Chen E, Gabrilovich DI (2018) Plasticity of myeloid-derived suppressor cells in cancer. Curr Opin Immunol 51:76–82
Zhu Y, Herndon JM, Sojka DK, Kim KW, Knolhoff BL, Zuo C, Cullinan DR, Luo J, Bearden AR, Lavine KJ, Yokoyama WM, Hawkins WG, Fields RC, Randolph GJ, DeNardo DG (2017) Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47(2):323–338.e6
Zhang B, Yao G, Zhang Y, Gao J, Yang B, Rao Z, Gao J (2011) M2-polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma. Clinics (Sao Paulo) 66(11):1879–1886
Fu Y, Moore XL, Lee MK, Fernández-Rojo MA, Parat MO, Parton RG, Meikle PJ, Sviridov D, Chin-Dusting JP (2012) Caveolin-1 plays a critical role in the differentiation of monocytes into macrophages. Arterioscler Thromb Vasc Biol 32(9):e117–125
Zhu L, Zhao Q, Yang T, Ding W, Zhao Y (2015) Cellular metabolism and macrophage functional polarization. Int Rev Immunol 34(1):82–100
Muppa P, Parrilha Terra SBS, Sharma A, Mansfield AS, Aubry MC, Bhinge K, Asiedu MK, de Andrade M, Janaki N, Murphy SJ, Nasir A, Van Keulen V, Vasmatzis G, Wigle DA, Yang P, Yi ES, Peikert T, Kosari F (2019) Immune cell infiltration may be a key determinant of long-term survival in small cell lung cancer. J Thorac Oncol 14(7):1286–1295
Ohri CM, Shikotra A, Green RH, Waller DA, Bradding P (2009) Macrophages within NSCLC tumour islets are predominantly of a cytotoxic M1 phenotype associated with extended survival. Eur Respir J 33(1):118–126
Oser MG, Niederst MJ, Sequist LV, Engelman JA (2015) Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol 16(4):e165–172
Morinaga R, Okamoto I, Furuta K, Kawano Y, Sekijima M, Dote K, Satou T, Nishio K, Fukuoka M, Nakagawa K (2007) Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer 58(3):411–413
Bhairavabhotla RK, Verm V, Tongaonkar H, Shastri S, Dinshaw K, Chiplunkar S (2007) Role of IL-10 in immune suppression in cervical cancer. Indian J Biochem Biophys 44(5):350–356
Koh B, Hufford MM, Sun X, Kaplan MH (2017) Etv5 regulates IL-10 Production in Th cells. J Immunol 198(5):2165–2171
Fioravanti J, Di Lucia P, Magini D, Moalli F, Boni C, Benechet AP, Fumagalli V, Inverso D, Vecchi A, Fiocchi A, Wieland S, Purcell R, Ferrari C, Chisari FV, Guidotti LG, Iannacone M (2017) Effector CD8+ T cell-derived interleukin-10 enhances acute liver immunopathology. J Hepatol 67(3):543–548
Li Y, Rong J, Qin J, He JY, Chen HG, Huang SH (2016) Micro RNA-98 interferes with expression interleukin-10 in peripheral B cells of patients with lung cancer. Sci Rep 6:32754
Soroosh P, Doherty TA, Duan W, Mehta AK, Choi H, Adams YF, Mikulski Z, Khorram N, Rosenthal P, Broide DH, Croft M (2013) Lungresident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance. J Exp Med 210:775–788
Duan MC, Han W, Jin PW, Wei YP, Wei Q, Zhang LM, Li JC (2015) Disturbed Th17/Treg balance in patients with non-small cell lung cancer. Inflammation 38(6):2156–2165
Whiteside TL (2012) What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol 22(4):327–334
Genin M, Clement F, Fattaccioli A, Raes M, Michiels C (2015) M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer. https://doi.org/10.1186/s12885-015-1546-9
Dijkgraaf EM, Heusinkveld M, Tummers B, Vogelpoel LT, Goedemans R, Jha V, Nortier JW, Welters MJ, Kroep JR, van der Burg SH (2013) Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res 73(8):2480–2492
Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, Seifi B, Mohammadi A, Afshari JT, Sahebkar A (2018) Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 233(9):6425–6440
Huang YK, Wang M, Sun Y, Di Costanzo N, Mitchell C, Achuthan A, Hamilton JA, Busuttil RA, Boussioutas A (2019) Macrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry. Nat Commun 10(1):3928
Funding
This work was supported by the National Natural Science Foundation of China (nos. 30972610, 81273240, 91742107, 81570002 and 81700027), National key research and development program (nos. 2017YFC0910000 and 2017YFD0501300), Department of Science and Technology of Jilin Province (no.20200403084SF, JLSWSRCZX2020-009, 20200901025SF, 20190101022JH, 2019J026, 20170622009JC, 2017C021, 2017J039, SXGJXX2017-8, JJKH20180197KJ, DBXM154-2018, 2018SCZWSZX-015).
Author information
Authors and Affiliations
Contributions
Xintong Hu conceived the manuscript. All authors wrote and edited the manuscript and approved its final version.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All participants provided their signed written informed consent. This study was approved by the Ethical Committee of the First Hospital of Jilin University (NO.2016–358).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Hu, X., Gu, Y., Zhao, S. et al. Increased IL-10+CD206+CD14+M2-like macrophages in alveolar lavage fluid of patients with small cell lung cancer. Cancer Immunol Immunother 69, 2547–2560 (2020). https://doi.org/10.1007/s00262-020-02639-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-020-02639-z