Impaired T-bet-pSTAT1α and perforin-mediated immune responses in the tumoral region of lung adenocarcinoma.
In spite of modern therapies for non-small-cell lung cancer (NSCLC), prognosis for many patients is still poor and survival rates are low. Immunotherapy is the possibility to improve the lung immune response surrounding the tumour. However, this approach requires detailed understanding of the local immune-responses of NSCLC patients.



We analysed samples from three different regions within the lungs of NSCLC patients, whereas we distinguished between patients suffering from adenocarcinoma and squamous cell carcinoma. Expression of type 1 T helper (Th1)/type 1 cytotoxic (Tc1) factors was assessed by quantitative real-time PCR, western blot analyses or immunohistochemistry. Cytotoxic cell activity of CD8(+) T cells was determined via co-culture with autologous tumour cells and apoptosis assay.



We found decreased levels of the transcription factor T-box expressed in T cells (T-bet or Tbx21) and of the downstream activated IFN-γ-dependent pSTAT1α isoform in the lung tumour areas of patients with NSCLC as compared with tumour-free control regions. In these patients, reduced T-bet and pSTAT1α levels were found associated with increased immunosuppressive markers like cytotoxic T lymphocyte-associated protein 4, programmed cell death 1 and with a suppression of the Th1 cell cytokine production and Tc1 cell activity.



These findings confirm a central role of T-bet in targeted immunotherapy for patients with NSCLC.
Department of Molecular Pneumology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.
Katerina
K
Andreev
Department of Molecular Pneumology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.|Department of Thoracic Surgery, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.
Denis Iulian
DI
Trufa
Department of Molecular Pneumology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.
Raphaela
R
Siegemund
Institute of Pathology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.
Ralf
R
Rieker
Institute of Pathology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.
Arndt
A
Hartmann
Institute of Anesthesiology, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054, Germany.
Joachim
J
Schmidt
Department of Thoracic Surgery, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.
Horia
H
Sirbu
Department of Molecular Pneumology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.
Susetta
S
Finotto
D000230:Adenocarcinoma / Q000276:immunology* / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000628:therapy; D016207:Cytokines / Q000032:analysis; D005260:Female; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3 / Q000032:analysis* / Q000235:genetics; D007371:Interferon-gamma / Q000032:analysis; D008175:Lung Neoplasms / Q000276:immunology* / Q000628:therapy; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D016612:Paraffin Embedding; D054353:Perforin / Q000032:analysis*; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis; D020033:Protein Isoforms / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D020825:T-Box Domain Proteins / Q000032:analysis; D055815:Young Adult; D000098815:T-bet Transcription Factor
D016207:Cytokines; C491199:EOMES protein, human; D050832:Interferon-Stimulated Gene Factor 3; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D020033:Protein Isoforms; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C079868:gamma interferon activation factor; D054353:Perforin; D007371:Interferon-gamma