Impact of the immune molecular profile of the tumor microenvironment on the prognosis of NSCLC

Ying,Hangjie; Hang,Qingqing; Cheng,Guoping; Yang,Shifeng; Lai,Xiaojing; Fang,Min

doi:10.3892/ol.2023.13717

Impact of the immune molecular profile of the tumor microenvironment on the prognosis of NSCLC

Authors:
- Hangjie Ying
- Qingqing Hang
- Guoping Cheng
- Shifeng Yang
- Xiaojing Lai
- Min Fang
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Affiliations: Zhejiang Cancer Institute, The Cancer Hospital of The University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China, Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China, Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
Published online on: February 14, 2023 https://doi.org/10.3892/ol.2023.13717
Article Number: 131
Copyright: © Ying et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to clarify the association between macrophages, tumor neo‑vessels and programmed cell death‑ligand 1 (PD‑L1) in the tumor microenvironment and the clinicopathological features of patients with non‑small cell lung cancer (NSCLC), and to explore the prognostic factors of stromal features in NSCLC. To determine this, tissue microarrays containing samples of 92 patients with NSCLC were studied using immunohistochemistry and immunofluorescence. The quantitative data demonstrated that in tumor islets, the number of CD68⁺ and CD206⁺ tumor‑associated macrophages (TAMs) was 8‑348 (median, 131) and 2‑220 (median, 52), respectively (P<0.001). In tumor stroma, the number of CD68⁺ and CD206⁺ TAMs was 23‑412 (median, 169) and 7‑358 (median, 81), respectively (P<0.001). The number of CD68+ TAMs in each location of the tumor islets and tumor stroma was significantly higher than that of CD206⁺ TAMs, and they were significantly correlated (P<0.0001). The quantitative density of CD105 and PD‑L1 in tumor tissues was 19‑368 (median, 156) and 9‑493 (median, 103), respectively. Survival analysis revealed that a high density of CD68⁺ TAMs in tumor stroma and islets and a high density of CD206⁺ TAMs and PD‑L1 in tumor stroma were associated with worse prognosis (both P<0.05). Collectively, the survival analysis demonstrated that the high‑density group was related to a worse prognosis regardless of combined neo‑vessels and PD‑L1 expression with the CD68⁺ TAMs in tumor islets and stroma, or CD206⁺ TAMs in tumor islets and stroma. To the best of our knowledge, the present study was the first to provide a multi‑component combined prognostic survival analysis of different types of macrophages in different regions with tumor neo‑vessels and PD‑L1, which demonstrated the importance of macrophages in tumor stroma.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
2	Liu X, Shen SL and Wang YP: Current ststus of comprehensive interventional therapy for advanced non-small cell lung cancer. Zhonghua Fei Bu Ji Bing Za Zhi (Dian Zi Ban). 10:486–489. 2017.(In Chinese).
3	Paget S: The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8:98–101. 1989.PubMed/NCBI
4	Catalano V, Turdo A, Di Franco S, Dieli F, Todaro M and Stassi G: Tumor and its microenvironment: A synergistic interplay. Semin Cancer Biol. 23:522–532. 2013. View Article : Google Scholar : PubMed/NCBI
5	Mosser DM and Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 8:958–969. 2008. View Article : Google Scholar : PubMed/NCBI
6	Schmieder A, Michel J, Schonhaar K, Goerdt S and Schledzewski K: Differentiation and gene expression profile of tumor-associated macrophages. Semin Cancer Biol. 22:289–297. 2012. View Article : Google Scholar : PubMed/NCBI
7	Pollard JW: Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 4:71–78. 2004. View Article : Google Scholar : PubMed/NCBI
8	Joshi N, Walter JM and Misharin AV: Alveolar macrophages. Cell Immunol. 330:86–90. 2018. View Article : Google Scholar : PubMed/NCBI
9	Falini B, Flenghi L, Pileri S, Bigerna B, Durkop H, Eitelbach F, Thiele J, Pacini R and Cavaliere A: PG-M1: A new monoclonal antibody directed against a fixative-resistant epitope on the macrophage-restricted form of the CD68 molecule. Am J Pathol. 142:1359–1372. 1993.PubMed/NCBI
10	Gordon S: Alternative activation of macrophages. Nat Rev Immunol. 3:23–35. 2003. View Article : Google Scholar : PubMed/NCBI
11	Dai F, Liu L, Che G, Yu N, Pu Q, Zhang S, Ma J, Ma L and You Z: The number and microlocalization of tumor-associated immune cells are associated with patient's survival time in non-small cell lung cancer. BMC Cancer. 10:2202010. View Article : Google Scholar : PubMed/NCBI
12	Li Z, Maeda D, Yoshida M, Umakoshi M, Nanjo H, Shiraishi K, Saito M, Kohno T, Konno H, Saito H, et al: The intratumoral distribution influences the prognostic impact of CD68- and CD204-positive macrophages in non-small cell lung cancer. Lung Cancer. 123:127–135. 2018. View Article : Google Scholar : PubMed/NCBI
13	Komohara Y, Jinushi M and Takeya M: Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 105:1–8. 2014. View Article : Google Scholar : PubMed/NCBI
14	Sumitomo R, Hirai T, Fujita M, Murakami H, Otake Y and Huang CL: M2 tumor-associated macrophages promote tumor progression in non-small-cell lung cancer. Exp Ther Med. 18:4490–4498. 2019.PubMed/NCBI
15	Hicklin DJ and Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 23:1011–1027. 2005. View Article : Google Scholar : PubMed/NCBI
16	Lin CY, Siow TY, Lin MH, Hsu YH, Tung YY, Jang T, Recht L and Chang C: Visualization of rodent brain tumor angiogenesis and effects of antiangiogenic treatment using 3D ΔR2-µMRA. Angiogenesis. 16:785–793. 2013. View Article : Google Scholar : PubMed/NCBI
17	Sajib S, Zahra FT, Lionakis MS, German NA and Mikelis CM: Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions. Angiogenesis. 21:1–14. 2018. View Article : Google Scholar : PubMed/NCBI
18	Li S, Xu HX, Wu CT, Wang WQ, Jin W, Gao HL, Li H, Zhang SR, Xu JZ, Qi ZH, et al: Angiogenesis in pancreatic cancer: Current research status and clinical implications. Angiogenesis. 22:15–36. 2019. View Article : Google Scholar : PubMed/NCBI
19	Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S and Gasparini G: Tumor angiogenesis: A new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst. 84:1875–1887. 1992. View Article : Google Scholar : PubMed/NCBI
20	Akagi K, Ikeda Y, Sumiyoshi Y, Kimura Y, Kinoshita J, Miyazaki M and Abe T: Estimation of angiogenesis with anti-CD105 immunostaining in the process of colorectal cancer development. Surgery. 131:S109–S113. 2002. View Article : Google Scholar : PubMed/NCBI
21	Wu TH, Li YY, Wu TL, Chang JWC, Chou WC, Hsieh LL, Chen JR and Yeh KY: Culture supernatants of different colon cancer cell lines induce specific phenotype switching and functional alteration of THP-1 cells. Cell Immunol. 290:107–115. 2014. View Article : Google Scholar : PubMed/NCBI
22	Yeo EJ, Cassetta L, Qian BZ, Lewkowich I, Li JF, Stefater JA III, Smith A, Wiechmann LS, Wang Y, Pollard JW and Lang RA: Myeloid WNT7b mediates the angiogenic switch and metastasis in breast cancer. Cancer Res. 74:2962–2973. 2014. View Article : Google Scholar : PubMed/NCBI
23	Ohba K, Miyata Y, Kanda S, Koga S, Hayashi T and Kanetake H: Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: Correlation with tumor associated macrophage and prognosis. J Urol. 174:461–465. 2005. View Article : Google Scholar : PubMed/NCBI
24	Allavena P, Sica A, Solinas G, Porta C and Mantovani A: The inflammatory micro-environment in tumor progression: The role of tumor-associated macrophages. Crit Rev Oncol Hematol. 66:1–9. 2008. View Article : Google Scholar : PubMed/NCBI
25	Han B, Li K, Zhao Y, Li B, Cheng Y, Zhou J, Lu Y, Shi Y, Wang Z, Jiang L, et al: Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: A multicentre, randomised phase II trial (ALTER0302). Br J Cancer. 118:654–661. 2018. View Article : Google Scholar : PubMed/NCBI
26	Murdoch C, Muthana M, Coffelt SB and Lewis CE: The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 8:618–631. 2008. View Article : Google Scholar : PubMed/NCBI
27	Anagnostou VK and Brahmer JR: Cancer immunotherapy: A future paradigm shift in the treatment of non-small cell lung cancer. Clin Cancer Res. 21:976–984. 2015. View Article : Google Scholar : PubMed/NCBI
28	Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V and Chouaib S: PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 211:781–790. 2014. View Article : Google Scholar : PubMed/NCBI
29	Dancau AM, Simon R, Mirlacher M and Sauter G: Tissue microarrays. Methods Mol Biol. 576:49–60. 2010. View Article : Google Scholar : PubMed/NCBI
30	Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WRR, Nicholson AG, Groome P, Mitchell A, Bolejack V, et al: The IASLC lung cancer staging project: Proposals for revision of the TNM stage groupings in the forthcoming (Eighth) edition of the TNM Classification for lung cancer. J Thorac Oncol. 11:39–51. 2016. View Article : Google Scholar : PubMed/NCBI
31	Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, Zhao YW and Wei YQ: Prognostic significance of tumor-associated macrophages in solid tumor: A meta-analysis of the literature. PLoS One. 7:e509462012. View Article : Google Scholar : PubMed/NCBI
32	Du ZY, Shi MH, Ji CH and Yu Y: Serum pleiotrophin could be an early indicator for diagnosis and prognosis of non-small cell lung cancer. Asian Pac J Cancer Prev. 16:1421–1425. 2015. View Article : Google Scholar : PubMed/NCBI
33	Keskin S, Kutluk AC and Tas F: Prognostic and predictive role of angiogenic markers in non- small cell lung cancer. Asian Pac J Cancer Prev. 20:733–736. 2019. View Article : Google Scholar : PubMed/NCBI
34	Huang W, Ran R, Shao B and Li H: Prognostic and clinicopathological value of PD-L1 expression in primary breast cancer: A meta-analysis. Breast Cancer Res Treat. 178:17–33. 2019. View Article : Google Scholar : PubMed/NCBI
35	Yagi T, Baba Y, Ishimoto T, Iwatsuki M, Miyamoto Y, Yoshida N, Watanabe M and Baba H: PD-L1 Expression, tumor-infiltrating lymphocytes, and clinical outcome in patients with surgically resected esophageal cancer. Ann Surg. 269:471–478. 2019. View Article : Google Scholar : PubMed/NCBI
36	Patel SP and Kurzrock R: PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 14:847–856. 2015. View Article : Google Scholar : PubMed/NCBI
37	Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al: Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. New Eng J Med. 373:123–135. 2015. View Article : Google Scholar : PubMed/NCBI
38	Muz B, de la Puente P, Azab F and Azab AK: The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl). 3:83–92. 2015. View Article : Google Scholar : PubMed/NCBI
39	Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A, Politi LS, Gentner B, Brown JL, Naldini L and De Palma M: Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell. 19:512–526. 2011. View Article : Google Scholar : PubMed/NCBI
40	Cooper WA, Tran T, Vilain RE, Madore J, Selinger CI, Kohonen-Corish M, Yip P, Yu B, O'Toole SA, McCaughan BC, et al: PD-L1 expression is a favorable prognostic factor in early stage non-small cell carcinoma. Lung Cancer. 89:181–188. 2015. View Article : Google Scholar : PubMed/NCBI
41	Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L and Rimm DL: In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res. 20:2773–2782. 2014. View Article : Google Scholar : PubMed/NCBI
42	Zheng Z, Bu Z, Liu X, Zhang L, Li Z, Wu A, Wu X, Cheng X, Xing X, Du H, et al: Level of circulating PD-L1 expression in patients with advanced gastric cancer and its clinical implications. Chin J Cancer Res. 26:104–111. 2014.PubMed/NCBI
43	Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X, Zlobec I, Eppenberger-Castori S, Tzankov A, Rosso R, et al: Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer. 49:2233–2242. 2013. View Article : Google Scholar : PubMed/NCBI
44	Sorensen SF, Zhou W, Dolled-Filhart M and Georgsen J: 1328ppd-L1 expression and survival among advanced non-small cell lung cancer (Nsclc) patients treated with chemotherapy. Ann Oncol. 25 (Suppl 4):iv467. 2014. View Article : Google Scholar : PubMed/NCBI
45	Li H, Xu Y, Wan B, Song Y, Zhan P, Hu Y, Zhang Q, Zhang F, Liu H, Li T, et al: The clinicopathological and prognostic significance of PD-L1 expression assessed by immunohistochemistry in lung cancer: A meta-analysis of 50 studies with 11,383 patients. Transl Lung Cancer Res. 8:429–449. 2019. View Article : Google Scholar : PubMed/NCBI
46	Keller MD, Neppl C, Irmak Y, Hall SR, Schmid RA, Langer R and Berezowska S: Adverse prognostic value of PD-L1 expression in primary resected pulmonary squamous cell carcinomas and paired mediastinal lymph node metastases. Mod Pathol. 31:101–110. 2018. View Article : Google Scholar : PubMed/NCBI
47	Igawa S, Sato Y, Ryuge S, Ichinoe M, Katono K, Hiyoshi Y, Otani S, Nagashio R, Nakashima H, Katagiri M, et al: Impact of PD-L1 expression in patients with surgically resected non-small-cell lung cancer. Oncology. 92:283–290. 2017. View Article : Google Scholar : PubMed/NCBI
48	Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL and Chen L: Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 4:127ra1372012. View Article : Google Scholar : PubMed/NCBI
49	Mandarano M, Bellezza G, Belladonna ML, Van den Eynde BJ, Chiari R, Vannucci J, Mondanelli G, Ludovini V, Ferri I, Bianconi F, et al: Assessment of TILs, IDO-1, and PD-L1 in resected non-small cell lung cancer: An immunohistochemical study with clinicopathological and prognostic implications. Virchows Arch. 474:159–168. 2019. View Article : Google Scholar : PubMed/NCBI
50	Sumitomo R, Hirai T, Fujita M, Murakami H, Otake Y and Huang CL: PD-L1 expression on tumor-infiltrating immune cells is highly associated with M2 TAM and aggressive malignant potential in patients with resected non-small cell lung cancer. Lung Cancer. 136:136–144. 2019. View Article : Google Scholar : PubMed/NCBI
51	Wen ZF, Liu H, Gao R, Zhou M, Ma J, Zhang Y, Zhao J, Chen Y, Zhang T, Huang F, et al: Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1. J Immunother Cancer. 6:1512018. View Article : Google Scholar : PubMed/NCBI