Immunosuppressive tumor microenvironment of usual interstitial pneumonia-associated squamous cell carcinoma of the lung

  • Takuya Ueda
  • Keiju Aokage
  • Hiroyoshi Nishikawa
  • Shinya Neri
  • Hiroshi Nakamura
  • Masato Sugano
  • Kenta Tane
  • Tomohiro Miyoshi
  • Motohiro Kojima
  • Satoshi Fujii
  • Takeshi Kuwata
  • Atsushi Ochiai
  • Masahiko Kusumoto
  • Kenji Suzuki
  • Masahiro Tsuboi
  • Genichiro Ishii
Original Article – Cancer Research

Abstract

Purpose

Patients with usual interstitial pneumonia (UIP) often develop lung cancer. However, the biological features of lung cancer associated with UIP remain unknown. The aim of this study was to elucidate the clinicopathological characteristics of UIP-associated squamous cell carcinoma (SqCC).

Methods

A total of 244 patients with p-stage I lung SqCC who underwent complete surgical resection were enrolled in this study. Clinicopathological differences between UIP-associated SqCC and non-UIP SqCC were examined. Moreover, we performed immunohistochemical studies to clarify the biological differences between these two groups.

Results

UIP-associated SqCC was detected in 19 patients (6.0%). Patients with UIP-associated SqCC tended to have shorter recurrence-free survival (RFS) (5-year RFS; UIP-associated SqCC 44% vs non-UIP SqCC 62%, p = 0.05). Immunohistochemical analysis revealed that the expression scores of cancer stem cell- and invasion-related molecules in cancer cells were not significantly different between the two groups. However, PD-L1 expression in cancer cells was significantly higher in UIP-associated SqCC (median score; 5.0 vs 0, p < 0.01). In the stroma of UIP-associated SqCC, the number of Foxp3+ tumor-infiltrating lymphocytes was significantly higher than that in non-UIP SqCC (median number 43/HPF vs 24/HPF, p < 0.01). In addition, CD8+/Foxp3+ T-cell ratio in UIP-associated SqCC was significantly lower than that in non-UIP SqCC (median ratio 1.8 vs 3.4, p < 0.01).

Conclusion

Our current study clearly revealed that the establishment of an immunosuppressive tumor microenvironment is a characteristic feature of UIP-associated SqCC, which can be correlated with poor prognosis in UIP-associated SqCC.

Keywords

Lung squamous cell carcinoma Usual interstitial pneumonia PD-L1 Tumor immunity Tumor microenvironment 

Abbreviations

ALDH-1

Aldehyde dehydrogenase 1

CAFs

Cancer-associated fibroblasts

CA IX

Carbonic anhydrase IX

CD8

Cluster of differentiation 8

CD204

Cluster of differentiation 204

Foxp3

Forkhead boxprotein P3

Glut-1

Glucose transporter 1

HPF

High-power field

IDO

Indoleamine 2,3-dioxygenase

IL-10

Interleukin 10

IPF

Idiopathic pulmonary fibrosis

LVI

Lymphovascular invasion

NSCLC

Non-small cell lung cancer

PD-1

Programmed cell death 1

PD-L1

Programmed cell death ligand 1

RFS

Recurrence-free survival

SqCC

Squamous cell carcinoma

TAMs

Tumor-associated macrophages

TGFβ

Transforming growth factor-β

Tregs

Regular T cells

UIP

Usual interstitial pneumonia

VEGF

Vascular endothelial growth factor

VPI

Visceral pleural invasion

Notes

Author contributions

Dr. Ueda: contributed to the design and coordination of the study, prepared the manuscript, and read and approved the final manuscript. Dr. Aokage: contributed to the design and coordination of the study, revised the article for important intellectual content, and read and approved the final manuscript. Dr. Neri: contributed to the design and coordination of the study, revised the article for important intellectual content, and read and approved the final manuscript. Dr. Nshikawa, Dr. Nakamura, Dr. Sugano, Dr. Tane, Dr. Miyoshi, Dr. Kojima, Dr. Fujii, Dr. Kuwata, Dr. Ochiai, Dr. Kusumoto, Dr. Suzuki, and Dr. Tsuboi: contributed to preparing the manuscript and read and approved the final manuscript. Dr. Ishii: contributed to the design and coordination of the study, revised the article for important intellectual content, and read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Comprehensive informed consent was obtained from all individual participants included in the study.

Supplementary material

432_2018_2602_MOESM1_ESM.tif (852 kb)
Supplementary material 1 (TIF 851 KB)
432_2018_2602_MOESM2_ESM.tif (101 kb)
Supplementary material 2 (TIF 101 KB)
432_2018_2602_MOESM3_ESM.docx (32 kb)
Supplementary material 3 (DOCX 32 KB)

References

  1. Archontogeorgis K, Steiropoulos P, Tzouvelekis A, Nena E, Bouros D (2012) Lung cancer and interstitial lung diseases: a systematic review Pulmonary medicine 2012.:315918  https://doi.org/10.1155/2012/315918
  2. ATS/ERS (2002) American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 277–304Google Scholar
  3. Azuma K et al (2014) Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann Oncol 25:1935–1940.  https://doi.org/10.1093/annonc/mdu242 CrossRefPubMedGoogle Scholar
  4. Cardone A, Tolino A, Zarcone R, Caracciolo GB, Tartaglia E (1997) Prognostic value of desmoplastic reaction and lymphocytic infiltration in the management of breast cancer. Panminerva Med 39:174–177PubMedGoogle Scholar
  5. Chen X, Subleski JJ, Kopf H, Howard OMZ, Mannel DN, Oppenheim JJ (2008) Expression of TNFR2 defines a maximally suppressive subset of mouse CD4(+)CD25(+)FoxP3(+) T regulatory cells: applicability to tumor-infiltrating T regulatory cells. J Immunol 180:6467–6471CrossRefPubMedPubMedCentralGoogle Scholar
  6. Goldstraw P et al (2007) The IASLC lung cancer staging project: proposals for the revision of the TNM stage groupings in the forthcoming (Seventh) edition of the TNM classification of malignant tumors (vol 8, pp 706–714, 2007). J Thorac Oncol 2:985–985CrossRefGoogle Scholar
  7. Guo Q, Sun Y, Yu S, Bai H, Zhao J, Zhuo M, Wang J (2017) Programmed cell death-ligand 1 (PD-L1) expression and fibroblast growth factor receptor 1 (FGFR1) amplification in stage III/IV lung squamous cell carcinoma (SQC). Thoracic Cancer 8:73–79.  https://doi.org/10.1111/1759-7714.12399 CrossRefPubMedGoogle Scholar
  8. Ishii G, Ochiai A, Neri S (2016) Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev 99:186–196.  https://doi.org/10.1016/j.addr.2015.07.007 CrossRefPubMedGoogle Scholar
  9. Karampitsakos T et al (2017) Lung cancer in patients with idiopathic pulmonary fibrosis. Pulm Pharmacol Ther.  https://doi.org/10.1016/j.pupt.2017.03.016 Google Scholar
  10. Le Jeune I, Gribbin J, West J, Smith C, Cullinan P, Hubbard R (2007) The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the. UK Respir Med 101:2534–2540.  https://doi.org/10.1016/j.rmed.2007.07.012 CrossRefPubMedGoogle Scholar
  11. Liu Y et al (2013) PD-L1 expression by neurons nearby tumors indicates better prognosis in glioblastoma patients. J Neurosci Off J Soc Neurosci 33:14231–14245.  https://doi.org/10.1523/JNEUROSCI.5812-12.2013 CrossRefGoogle Scholar
  12. Mahoney KM, Rennert PD, Freeman GJ (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14:561–584.  https://doi.org/10.1038/nrd4591 CrossRefPubMedGoogle Scholar
  13. Matsushita H, Tanaka S, Saiki Y, Hara M, Nakata K, Tanimura S, Banba J (1995) Lung cancer associated with usual interstitial pneumonia. Pathol Int 45:925–932.  https://doi.org/10.1111/j.1440-1827.1995.tb03417.x CrossRefPubMedGoogle Scholar
  14. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG (2011) High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol 28:682–688.  https://doi.org/10.1007/s12032-010-9515-2 CrossRefPubMedGoogle Scholar
  15. Nagai ACA, Nakadate T, Konno K (1992) Lung cancer in patients with idiopathic pulmonary fibrosis. Tohoku J Exp Med 167:231–237CrossRefPubMedGoogle Scholar
  16. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tisty TD, Cunha GR (1999) Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Can Res 59:5002–5011Google Scholar
  17. Ono S et al (2013) Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated. Fibroblast Phenotype Chest 143:963–970.  https://doi.org/10.1378/chest.12-0913 PubMedGoogle Scholar
  18. Orimo A et al. (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 121:335–348  https://doi.org/10.1016/j.cell.2005.02.034 CrossRefPubMedGoogle Scholar
  19. Ozawa Y et al (2009) Cumulative incidence of and predictive factors for lung cancer in. IPF Respirol 14:723–728.  https://doi.org/10.1111/j.1440-1843.2009.01547.x CrossRefGoogle Scholar
  20. Pardo A et al (2005) Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. PLoS Med 2:e251.  https://doi.org/10.1371/journal.pmed.0020251 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Parmar H (2004) Epithelial-stromal interactions in the mouse and human mammary gland in vivo. Endocrine Rel Cancer 11:437–458.  https://doi.org/10.1677/erc.1.00659 CrossRefGoogle Scholar
  22. Petersen RP, Campa MJ, Sperlazza J, Conlon D, Joshi MB, Harpole DH Jr, Patz EF Jr (2006) Tumor infiltrating Foxp3 + regulatory T-cells are associated with recurrence in pathologic stage I. NSCLC patients Cancer 107:2866–2872.  https://doi.org/10.1002/cncr.22282 PubMedGoogle Scholar
  23. Raghu G et al (2011) An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 183:788–824.  https://doi.org/10.1164/rccm.2009-040GL CrossRefPubMedPubMedCentralGoogle Scholar
  24. Sato T et al. (2015) Long-term results and predictors of survival after surgical resection of patients with lung cancer and interstitial lung diseases J Thor Cardiovasc Surg 149:64–69.  https://doi.org/10.1016/j.jtcvs.2014.08.086 (70 e61–62)CrossRefGoogle Scholar
  25. Shang B, Liu Y, Jiang SJ, Liu Y (2015) Prognostic value of tumor-infiltrating FoxP3 + regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep 5:15179.  https://doi.org/10.1038/srep15179 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Takada K et al (2017) The expression of PD-L1 protein as a prognostic factor in lung squamous cell carcinoma. Lung Cancer 104:7–15.  https://doi.org/10.1016/j.lungcan.2016.12.006 CrossRefPubMedGoogle Scholar
  27. Tomassetti S et al (2015) The impact of lung cancer on survival of idiopathic pulmonary. Fibrosis CHEST 147:157–164.  https://doi.org/10.1378/chest.14-0359 PubMedGoogle Scholar
  28. Travis WDBE, Burke AP et al. (2015) The 2015 World Health Organization (WHO) Classification of Tumors of the Lung, Pleura, Thymus and Heart. LyonGoogle Scholar
  29. Wang A et al (2015) The prognostic value of PD-L1 expression for non-small cell lung cancer patients: a meta-analysis. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol 41:450–456.  https://doi.org/10.1016/j.ejso.2015.01.020 Google Scholar
  30. Wang X, Teng F, Kong L, Yu J (2016) PD-L1 expression in human cancers and its association with clinical outcomes. OncoTargets Therapy 9:5023–5039.  https://doi.org/10.2147/OTT.S105862 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Zheng Z et al. (2014) Level of circulating PD-L1 expression in patients with advanced gastric cancer and its clinical implications. Chin J Cancer Res. 26:104–111  https://doi.org/10.3978/j.issn.1000-9604.2014.02.08 PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pathology, Exploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
  2. 2.Department of Thoracic SurgeryNational Cancer Center Hospital EastKashiwaJapan
  3. 3.Department of Pathology and Clinical LaboratoriesNational Cancer Center Hospital EastKashiwaJapan
  4. 4.Departments of General Thoracic SurgeryJuntendo University School of MedicineTokyoJapan
  5. 5.Division of Cancer ImmunologyExploratory Oncology Research and Clinical Trial Center, National Cancer CenterKashiwaJapan
  6. 6.Department of Thoracic SurgeryKyoto University Graduate School of MedicineKyotoJapan
  7. 7.Exploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
  8. 8.Department of Diagnostic RadiologyNational Cancer Center Hospital EastChibaJapan

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