Tumor-associated metabolic and inflammatory responses in early stage non-small cell lung cancer: Local patterns and prognostic significance
INTRODUCTION: Non-small cell lung cancer (NSCLC) patients diagnosed in early stage and surgically-treated have five-year mortality rate >20%. The identification of biomarkers able to predict progression and death may help to identify patients needing closer follow-up. METHODS: A retrospective cohort of early-stage surgically-treated NSCLC patients enrolled in the International Association for the Study of Lung Cancer (IASLC) Staging Project was created, and tissue Microarrays (TMAs) were constructed with tumor and non-tumor lung tissue. Pentose phosphate pathway (PPP) proteins (transketolase [TKT] and transketolase-like 1 [TKTL1]), inflammatory markers (cyclooxygenase-2 [COX-2], tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL1β], nuclear factor kappa-light-chain-enhancer of activated B cells [NFκB]-p65 and antigen Ki-67), and programmed death-ligand 1 (PDL1) were measured by immunohistochemistry. RESULTS: NSCLC patients with adenocarcinoma (ADC) or squamous cell carcinoma (SCC) were included in the study (n = 199). TKT and TKTL1 were significantly higher in ADC than in non-tumor tissue (p 30% above those of non-tumor tissue (p < 0.001). PDL1 analysis showed a higher percentage of positivity in ADC than in non-tumor tissue (p < 0.001). Multivariate Cox proportional hazards modeling confirmed that high IL1β level in tumor tissue was independently associated with 3-year mortality in NSCLC [HR = 2.05, 95% CI (1.1-3.7), p = 0.019], a relationship driven by ADC subtype. CONCLUSION: This study confirms an increase in metabolic activity and an inflammatory response in tumor tissue of early stage NSCLC, and a significant relationship between high levels of IL1β in the tumor and poor prognosis in ADC. ; This study was funded by PII Oncología Torácica from Sociedad Española de Neumología y Cirugía Torácica (SEPAR), FIS 12/02040, FIS 12/02534 and FIS 12/01310 from the Instituto de Salud Carlos III and Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES). CIBERES is an initiative of the Instituto de Salud Carlos III. This work was also supported by grants to E.M. and M.C. from Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR)—Generalitat de Catalunya, (2014 GRC-801/2017 GRC-716 and 2014 SGR-1017/2017 SGR-1033), ICREA Foundation (ICREA Academia) and MINECO from the Spanish Government and FEDER funds (SAF2014‐56059‐R, SAF2015‐70270‐REDT, SAF2017-89673-R, European Commission FEDER—Una manera de hacer Europa), and to C.B. from AGAUR-Generalitat de Catalunya (FI-DGR2014). M.C. also received support from CB17/04/00023 from the Instituto de Salud Carlos III and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHD). CIBERHD is an initiative of the Instituto de Salud Carlos III. Financial support was also provided by the European Regional Development Fund (ERDF) and CERCA Programme / Generalitat de Catalunya.