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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
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
References
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
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 277–304
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
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 39:174–177
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 180:6467–6471
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 2:985–985
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
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
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
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
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
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
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
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
Nagai ACA, Nakadate T, Konno K (1992) Lung cancer in patients with idiopathic pulmonary fibrosis. Tohoku J Exp Med 167:231–237
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 59:5002–5011
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
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
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
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
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
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
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
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)
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
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
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
Travis WDBE, Burke AP et al. (2015) The 2015 World Health Organization (WHO) Classification of Tumors of the Lung, Pleura, Thymus and Heart. Lyon
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
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
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
Funding
This work was supported in part by the National Cancer Center Research and Development Fund (28-seeds-2), the Foundation for the Promotion of Cancer Research and JSPS KAKENHI (16H05311).
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
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.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Ueda, T., Aokage, K., Nishikawa, H. et al. Immunosuppressive tumor microenvironment of usual interstitial pneumonia-associated squamous cell carcinoma of the lung. J Cancer Res Clin Oncol 144, 835–844 (2018). https://doi.org/10.1007/s00432-018-2602-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-018-2602-z