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Clinicopathological significance of peritumoral alveolar macrophages in patients with resected early-stage lung squamous cell carcinoma

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Abstract

Introduction

This study aimed to clarify the correlation between the number of AMs and prognosis and to examine the gene expression of AMs in lung squamous cell carcinoma (SqCC).

Methods

We reviewed 124 stage I lung SqCC cases in our hospital and 139 stage I lung SqCC cases in The Cancer Genome Atlas (TCGA) cohort in this study. We counted the number of AMs in the peritumoral lung field (P-AMs) and in the lung field distant from the tumor (D-AMs). Moreover, we performed a novel ex vivo bronchoalveolar lavage fluid (BALF) analysis to select AMs from surgically resected lung SqCC cases and examined the expression of IL10, CCL2, IL6, TGFβ, and TNFα (n = 3).

Results

Patients with high P-AMs had significantly shorter overall survival (OS) (p < 0.01); however, patients with high D-AMs did not have significantly shorter OS. Moreover, in TCGA cohort, patients with high P-AMs had a significantly shorter OS (p < 0.01). In multivariate analysis, a higher number of P-AMs were an independent poor prognostic factor (p = 0.02). Ex vivo BALF analysis revealed that AMs collected from the tumor vicinity showed higher expression of IL10 and CCL2 than AMs from distant lung fields in all 3 cases (IL-10: 2.2-, 3.0-, and 10.0-fold; CCL-2: 3.0-, 3.1-, and 3.2-fold). Moreover, the addition of recombinant CCL2 significantly increased the proliferation of RERF-LC-AI, a lung SqCC cell line.

Conclusion

The current results indicated the prognostic impact of the number of peritumoral AMs and suggested the importance of the peritumoral tumor microenvironment in lung SqCC progression.

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Date availability

The datasets generated during and/or analyzed during the current study are available in the Cancer Genome Atlas repository, “https://portal.gdc.cancer.gov/

References

  1. Hyuna S, Jacques F, Rebecca LS et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. https://doi.org/10.3322/caac.21660

    Article  Google Scholar 

  2. National Comprehensive Cancer Network (2022) NCCN clinical practice guidelines in oncology non-small cell lung cancer. Version 5. (https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf) Accessed 2022 October 7

  3. Samantha T, Joachim P et al (2020) Validation of the 8th lung cancer TNM classification and clinical staging system in a German cohort of surgically resected patients. Innov Surg Sci 5(1–2):1–9. https://doi.org/10.1515/iss-2020-0010

    Article  Google Scholar 

  4. Åsa KÖ, Ann RH, Daniel N et al (2019) The immune microenvironment in non-small cell lung cancer is predictive of prognosis after surgery. Mol Oncol 13(5):1166–1179. https://doi.org/10.1002/1878-0261.12475

    Article  CAS  Google Scholar 

  5. Ishii G, Ochiai A, Neri S (2016) Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev 99(Pt B):186–196. https://doi.org/10.1016/j.addr.2015.07.007

    Article  CAS  PubMed  Google Scholar 

  6. Dan Su, Gao Wu, Xiong R et al (2021) Tumor immune microenvironment characteristics and their prognostic value in non-small-cell lung cancer. Front Oncol 11:634059. https://doi.org/10.3389/fonc.2021.634059

    Article  Google Scholar 

  7. Alberto M, Federica M, Alberto M et al (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14(7):399–416. https://doi.org/10.1038/nrclinonc.2016.217

    Article  CAS  Google Scholar 

  8. Yi-C W, Yu-S W, Chia-Y H et al (2018) USP24 induces IL-6 in tumor-associated microenvironment by stabilizing p300 and β-TrCP and promotes cancer malignancy. Nat Commun 9(1):3996. https://doi.org/10.1038/s41467-018-06178-1

    Article  CAS  Google Scholar 

  9. Luca C, Stamatina F, Andrew HS et al (2019) Human tumor-associated macrophages and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell 35(4):588–602. https://doi.org/10.1016/j.ccell.2019.02.009

    Article  CAS  Google Scholar 

  10. Mitsi E, Kamng’ona R, Rylance J et al (2018) Human alveolar macrophages predominately express combined classical M1 and M2 surface markers in steady state. Respir Res 19(1):66. https://doi.org/10.1186/s12931-018-0777-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Byrne AJ, Mathie SA, Gregory LG et al (2015) Pulmonary macrophages: key players in the innate defence of the airways. Thorax 70(12):1189–1196. https://doi.org/10.1136/thoraxjnl-2015-207020

    Article  PubMed  Google Scholar 

  12. Lim PN, Cervantes MM, Pham LK et al (2021) Alveolar macrophages: novel therapeutic targets for respiratory diseases. Expert Rev Mol Med 23:e18. https://doi.org/10.1017/erm.2021.21

    Article  CAS  PubMed  Google Scholar 

  13. Casanova-Acebes M, Dalla E, Leader AM et al (2021) Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells. Nature. https://doi.org/10.1038/s41586-021-03651-8

    Article  PubMed  PubMed Central  Google Scholar 

  14. Noritake O, Aokage K, Suzuki A et al (2022) Prognostic impact of the number of peritumoral alveolar macrophages in patients with stage I lung adenocarcinoma. J Cancer Res Clin Oncol. https://doi.org/10.1007/s00432-022-04056-4

    Article  PubMed  Google Scholar 

  15. Nosaka T, Baba T, Tanabe Y et al (2018) Alveolar macrophages drive hepatocellular carcinoma lung metastasis by generating leukotriene B 4. J Immunol 200(5):1839–1852. https://doi.org/10.4049/jimmunol.1700544

    Article  CAS  PubMed  Google Scholar 

  16. Li Y, Yi Z (2017) Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol 10(1):58. https://doi.org/10.1186/s13045-017-0430-2

    Article  CAS  Google Scholar 

  17. Jayasingam SD, Citartan M, Thang TH et al (2020) Evaluating the polarization of tumor-associated macrophages into M1 and M2 phenotypes in human cancer tissue: technicalities and challenges in routine clinical practice. Front Oncol 9:1512. https://doi.org/10.3389/fonc.2019.01512

    Article  PubMed  PubMed Central  Google Scholar 

  18. WHO Classification of Tumours Editorial Board (2021) WHO Classification of Tumours, 5th edn. World Health Organization, Geneva

    Google Scholar 

  19. Goldstraw P, Chansky K, Crowley J et al (2016) 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(1):39–51. https://doi.org/10.1016/j.jtho.2015.09.009

    Article  PubMed  Google Scholar 

  20. Nouno T, Okamoto M, Ohnishi K et al (2019) Elevation of pulmonary CD163+and CD204+macrophages is associated with the clinical course of idiopathic pulmonary fibrosis patients. J Thorac Dis 11(9):4005–4017. https://doi.org/10.21037/jtd.2019.09.03

    Article  PubMed  PubMed Central  Google Scholar 

  21. Colaprico A, Silva TC, Olsen C et al (2016) TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res 44:e7

    Article  Google Scholar 

  22. Morgan M, Obenchain V, Hester J et al (2020) Summarized experiment: summarized experiment container. R package version 1(18):2

    Google Scholar 

  23. Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550

    Article  PubMed  PubMed Central  Google Scholar 

  24. Warnes GR, Bolker B, Bonebakker L et al (2016) gplots: various R programming tools for plotting data. R package version 3:4

    Google Scholar 

  25. Gentleman R, Carey V, Huber W, et al (2020): genefilter: methods for filtering genes from high-throughput experiments. R package version 1.70.0.

  26. Zhou Y, Zhou B, Pache L, Chang M et al (2019) Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. https://doi.org/10.1038/s41467-019-09234-6

    Article  PubMed  PubMed Central  Google Scholar 

  27. Iriki T, Ohnishi K, Fujiwara Y et al (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. https://doi.org/10.1016/j.lungcan.2017.01.003

    Article  PubMed  Google Scholar 

  28. Hao Q, Vadgama JV, Wang P (2020) CCL2/CCR2 signaling in cancer pathogenesis. Cell Commun Signal 18(1):82. https://doi.org/10.1186/s12964-020-00589-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Qi X, Li Q, Che X et al (2022) Application of regulatory cell death in cancer: based on targeted therapy and immunotherapy. Front Immunol 13:837293. https://doi.org/10.3389/fimmu.2022.837293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Qi L, Yu H, Zhang Y et al (2016) IL-10 secreted by M2 macrophage promoted tumorigenesis through interaction with JAK2 in glioma. Oncotarget 7(44):71673–71685. https://doi.org/10.18632/oncotarget.12317

    Article  PubMed  PubMed Central  Google Scholar 

  31. Anfray C, Ummarino A, Andón FT et al (2020) Current strategies to target tumor-associated-macrophages to improve anti-tumor immune responses. Cells 9(1):46. https://doi.org/10.3390/cells9010046

    Article  CAS  Google Scholar 

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Funding

This work was supported in part by National cancer center research fund (2020-A-9) and JSPS KAKENHI (21H02931).

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Authors and Affiliations

  1. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Yu Tanaka, Tokiko Nakai, Yosuke Kagawa, Osamu Noritake, Tetsuro Taki, Saori Miyazaki, Naoya Sakamoto, Shingo Sakashita, Motohiro Kojima, Reiko Watanbe & Genichiro Ishii

  2. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Yu Tanaka, Yosuke Kagawa, Tetsuya Sakai, Yuji Shibata, Hiroki Izumi, Kaname Nosaki, Hibiki Udagawa, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh & Koichi Goto

  3. Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Yu Tanaka & Genichiro Ishii

  4. Department of Computational Biology and Medical Sciences, The University of Tokyo, Kashiwa, Chiba, Japan

    Ayako Suzuki

  5. Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Osamu Noritake & Masahiro Tsuboi

  6. Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan

    Hiroko Hashimoto & Genichiro Ishii

  7. Division of Pathology, Exploratory Oncology Research, and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan

    Naoya Sakamoto, Shingo Sakashita & Motohiro Kojima

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  1. Yu Tanaka
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Contributions

Material preparation, data collection, and analysis were performed by YT, AS, and HH. The experimental designs was developed by HH and GI. The first draft of the manuscript was written by YT. The conduct of this study was supervised by GI. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Genichiro Ishii.

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Competing interests

T. Sakai reports grants from AMGEN outside the submitted work; personal fees from AstraZeneca, Chugai Pharmaceutical, Novartis, MSD, Merck and Themo Fisher Scientific outside the submitted work. Y. Shibata reports grants from Ono Pharmaceutical Co., Ltd. and MSD outside the submitted work; personal fees from Pfizer Inc., Bristol-Myers Squibb K.K., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Merck, Takeda Pharmaceutical, Chugai Pharmaceutical. H. Izumi reports grants from Amgen Inc, Takeda Pharmaceutical Co., AstraZeneca, Eisai and Ono Pharmaceutical Company outside the submitted work; personal fees from Amgen Inc, Ono Pharmaceutical Company, Chugai Pharmaceutical Co., AstraZeneca, Merck Biopharma Co., Takeda Pharmaceutical Co. and Eisai. H. Udagawa reports grants from Takeda Pharmaceutical, and Boehringer Ingelheim GmbH outside the submitted work. Y. Zenke reports grants and personal fees from AstraZeneca, MSD, and Amgen; personal fees from Bristol-Myers Squibb, Lilly, Chugai, Ono Pharmaceutical, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, Novartis, Nippon Kayaku, and Kyowa Kirin; and grants from Merck and Daiichi Sankyo outside the submitted work. S. Matsumoto reports grants and personal fees from Merck; personal fees from Eli Lilly, AstraZeneca, Chugai Pharmaceutical, ThermoFisher Scientific, Riken Genesis, Guardant Health, Novartis Pharma, and Amgen; and grants from Janssen Pharmaceutical outside the submitted work. K. Yoh reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Lilly, Taiho, and Takeda; personal fees from Bristol-Myers Squibb, Janssen, Kyowa Kirin, and Novartis; and grants from AbbVie, MSD, and Pfizer outside the submitted work. M Tsuboi reports from Boehringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical CO.,LTD, Bristol-Myers Squibb KK, Eli Lilly Japan, Novartis, BMG Inc. and MiRXES Japan outside the submitted work; and personal fees from AstraZeneca, Chugai Pharmaceutical CO.,LTD, MSD, Novartis, Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical CO.,LTD, Taiho Pharma, Medtronic Japan, Ono Pharmaceutical CO.,LTD, MSD, Bristol-Myers Squibb KK and Teijin Pharma outside the submitted work. K. Goto reports grants from Merck, Takeda Pharmaceutical, Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Janssen, Kyowa Kirin, Lilly, Medical & Biological Laboratories, MSD, Novartis, Ono, Pfizer, Sumitomo Dainippon, Bayer Yakuhin Ltd., Haihe Biopharma Co. Ltd., Ignyta Inc., Kissei Pharmaceutical Co. Ltd., Life Technologies Japan Ltd., Loxo Oncology Inc., Merus N.V., NEC Corporation., Pfizer Japan Inc., Spectrum Pharmaceuticals Inc., Sysmex Corporation, Turning Point Therapeutics Inc., and Taiho and nonfinancial support from Guardant Health Inc. during the conduct of the study as well as grants and personal fees from Amgen, Amgen K.K., Amgen Astellas BioPharma K.K., AstraZeneca K.K., Boehringer Ingelheim Japan Inc., BristolMyers Squibb K.K., Blueprint Medicines Corporation, Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Merck Biopharma Co. Ltd., MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd. and personal fees from Amoy Diagnostics Co. Ltd., Bayer U.S., Guardant Health Inc., Thermo Fisher Scientific K.K., Medpace Japan K.K., and Otsuka Pharmaceutical Co. Ltd. outside the submitted work. G. Ishii report grands from DAIICHI SANKYO, INC., ONO PHARMACEUTICAL CO.,LTD., Noile-Immune Biotech Takeda Pharmaceutical Company Limited, Sumitomo Dainippon Pharma Co.,Ltd., Nihon Medi-Physics Co.,Ltd. Indivumed GmbH H.U. Group Research Institute; personal fees from Roche Diagnostics K.K., CHUGAI PHARMACEUTICAL CO., LTD., Novartis International AG, Oncolys BioPharma Inc., DAIICHI SANKYO, INC., Eli Lilly Japan K.K., Takeda Pharmaceutical Company Limited, AstraZeneca, RIKEN GENESIS CO., LTD. No disclosures were reported by the other authors.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of National cancer center hospital east (2020-343).

Consent to participate

This study was conducted on patients who provided blanket consent.

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Tanaka, Y., Nakai, T., Suzuki, A. et al. Clinicopathological significance of peritumoral alveolar macrophages in patients with resected early-stage lung squamous cell carcinoma. Cancer Immunol Immunother 72, 2205–2215 (2023). https://doi.org/10.1007/s00262-023-03393-8

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