Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients.

Foteinos-Ioannis D Dimitrakopoulos,Anastasia E Kottorou,Chrisoula Scopa,Haralabos P Kalofonos,Vassiliki Tzelepi,Angelos Koutras,Thomas Makatsoris,Melpomeni Kalofonou,Anna G Antonacopoulou,Nikolaos Panagopoulos,Dimitrios Dougenis

doi:10.3390/jcm8050741

Abstract

An increasing number of studies implicates the NF-κB (Nuclear Factor of kappa light chain gene enhancer in B cells) alternative pathway in non-small-cell lung cancer (NSCLC). We assessed the clinical significance of CD40 (Tumor necrosis factor receptor superfamily member 5, TNFRSF5), BAFFR (B-cell activating factor receptor), RANK (Receptor activator of NF-κB) and LTβR (lymphotoxin β receptor) receptors, which activate the alternative pathway of NF-κB, in NSCLC. Evaluation of CD40, BAFFR, RANK and LTβR expression was performed based on the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, while protein expression was assessed by immunohistochemistry in specimens from 119 operated NSCLC patients. CD40 gene overexpression was correlated with improved five-year overall survival (OS) (p < 0.001), while increased BAFFR and LTβR mRNA levels were associated with worse OS in patients with adenocarcinomas (p < 0.001 and p < 0.001, respectively). Similarly, patients with adenocarcinomas exhibited a negative correlation between membranous BAFFR protein expression in carcinoma cells and three- and five-year survival (p = 0.021; HR, 4.977 and p = 0.030; HR, 3.358, respectively) as well as between BAFFR protein overexpression in cancer-associated fibroblasts (CAFs) and two-year survival (p = 0.036; HR, 1.983). Patients with increased LTβR nuclear protein staining or stage II patients with lower cytoplasmic LTβR protein expression had worse five-year OS (p = 0.039 and p = 0.008, respectively). Moreover, CD40 protein expression in tumor infiltrating lymphocytes (TILs) and CAFs was positively associated with metastatic spread while BAFFR protein expression in CAFs was negatively associated with bone metastasis (p = 0.041). Our data suggests that CD40, BAFFR, RANK and LTβR play an important role in NSCLC and further supports the role of NF-κB alternative pathway in NSCLC.

Highlights

The Nuclear Factor of kappa light chain gene enhancer in B cells (NF-κB) remains one of the most studied transcription factors in cancer biology due to its pivotal role in many cellular functions such as inflammation, metastasis, angiogenesis, metabolism, epithelial-mesenchymal transition and tumor cell survival [1]
We investigated the expression profiles of CD40, BAFFR, RANK and LTβR in non-small-cell lung cancer (NSCLC) tissue specimens and their significance on the clinical outcome
One of the major findings of our study is the deregulation of the CD40 and BAFFR protein expression in NSCLC

Summary

Introduction

The Nuclear Factor of kappa light chain gene enhancer in B cells (NF-κB) remains one of the most studied transcription factors in cancer biology due to its pivotal role in many cellular functions such as inflammation, metastasis, angiogenesis, metabolism, epithelial-mesenchymal transition and tumor cell survival [1]. The role of NF-κB in non-small-cell lung cancer (NSCLC) is well-documented and it has mainly been involved in proliferation, apoptosis, angiogenesis, inflammation and metastasis [4]. Overexpression of the four main intracellular players of the alternative pathway (NF-κB2, RelB (transcription factor RelB), NIK (Mitogen-activated protein kinase kinase kinase 14) and Bcl (B-cell lymphoma 3 protein) has been identified in primary NSCLC compared to normal tissues and association of their expression with lymph node infiltration and overall survival (OS) has been revealed [6,7,8]. We have previously reported that genetic variations of NF-κB2 and BCL3 are related to lung cancer risk and OS [6,9]

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