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



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).


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.


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).


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.


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



Aldehyde dehydrogenase 1


Cancer-associated fibroblasts


Carbonic anhydrase IX


Cluster of differentiation 8


Cluster of differentiation 204


Forkhead boxprotein P3


Glucose transporter 1


High-power field


Indoleamine 2,3-dioxygenase


Interleukin 10


Idiopathic pulmonary fibrosis


Lymphovascular invasion


Non-small cell lung cancer


Programmed cell death 1


Programmed cell death ligand 1


Recurrence-free survival


Squamous cell carcinoma


Tumor-associated macrophages


Transforming growth factor-β


Regular T cells


Usual interstitial pneumonia


Vascular endothelial growth factor


Visceral pleural invasion


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.


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).

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

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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)


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Copyright information

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

Authors and Affiliations

  • Takuya Ueda
    • 1
    • 2
    • 3
    • 4
  • Keiju Aokage
    • 2
  • Hiroyoshi Nishikawa
    • 5
  • Shinya Neri
    • 6
  • Hiroshi Nakamura
    • 1
    • 3
    • 4
  • Masato Sugano
    • 3
  • Kenta Tane
    • 2
  • Tomohiro Miyoshi
    • 2
  • Motohiro Kojima
    • 1
  • Satoshi Fujii
    • 1
  • Takeshi Kuwata
    • 3
  • Atsushi Ochiai
    • 7
  • Masahiko Kusumoto
    • 8
  • Kenji Suzuki
    • 4
  • Masahiro Tsuboi
    • 2
  • Genichiro Ishii
    • 1
  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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