Abstract
Tumor necrosis factor-alpha (TNFα) can bind two distinct receptors (TNFR1/2). The transmembrane form (tmTNFα) preferentially binds to TNFR2. Upon tmTNFα cleavage by the TNF-alpha-converting enzyme (TACE), its soluble (sTNFα) form is released with higher affinity for TNFR1. This assortment empowers TNFα with a plethora of opposing roles in the processes of tumor cell survival (and apoptosis) and anti-tumor immune stimulation (and suppression), in addition to angiogenesis and metastases. Its functions and biomarker potential to predict cancer progression and response to immunotherapy are reviewed here, with a focus on lung cancer. By mining existing sequencing data, we further demonstrate that the expression levels of TNF and TACE are significantly decreased in lung adenocarcinoma patients, while the TNFR1/TNFR2 balance are increased. We conclude that the biomarker potential of TNFα alone will most likely not provide conclusive findings, but that TACE could have a key role along with the delicate balance of sTNFα/tmTNFα as well as TNFR1/TNFR2, hence stressing the importance of more research into the potential of rationalized treatments that combine TNFα pathway modulators with immunotherapy for lung cancer patients.
Highlights
TNFR1/TNFR2, stressing the importance of more research into the potential of rationalized treatments that combine TNFα pathway modulators with immunotherapy for lung cancer patients
Using an online available RNAseq dataset on CD8+ T cells sorted out of non-small cell lung cancer (NSCLC) patients’ peripheral blood mononuclear cells before and during anti-programmed death-1 (PD-1) mAb therapy [131], we were able to support the notion that increased levels of sTNFα could be linked to improved anti-PD-1 treatment response, as we found a non-significant increase in tumor necrosis factor (TNF)-alpha-converting enzyme (TACE) expression within the responder group linked to more release of sTNFα from its tmTNFα form (Figure 2E)
The multitude of contradictory findings currently poses a stalemate for TNFα pathwayaffecting strategies in combination with immunotherapy to treat lung cancer and suggests the need for additional research into biomarkers to guide rationalized therapy combinations
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. About 60 years ago, it was reported that bacterial endotoxin administration to mice resulted in the release of a serological protein with necrotic anti-tumor activity at high concentrations Due to the latter characteristic, this protein was termed tumor necrosis factor (TNF) [1] and considered a breakthrough for cancer therapy. TNFα is represented by a trimer of 17.35 kDa monomers, folded into a rigid bell-shaped “jelly roll” composed of antiparallel filaments [3]. It exists in two forms: a transmembrane form (tmTNFα) next to a soluble (sTNFα) form. The complexity of these findings tempered the original enthusiasm for TNFα as a breakthrough molecule for cancer therapy
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