Abstract
Treatment of advanced (metastatic) non-small-cell lung cancer (NSCLC) is currently mainly based on immunotherapy with antibodies against PD-1 or PD-L1, alone, or in combination with chemotherapy. In locally advanced NSCLC and in early resected stages, immunotherapy is also employed. Tumor PD-L1 expression by immunohistochemistry is considered the standard practice. Response rate is low, with median progression free survival very short in the vast majority of studies reported. Herein, numerous biological facets of NSCLC are described involving driver genetic lesions, mutations ad fusions, PD-L1 glycosylation, ferroptosis and metabolic rewiring in NSCLC and lung adenocarcinoma (LUAD). Novel concepts, such as immune-transmitters and the effect of neurotransmitters in immune evasion and tumor growth, the nascent relevance of necroptosis and pyroptosis, possible new biomarkers, such as gasdermin D and gasdermin E, the conundrum of K-Ras mutations in LUADs, with the growing recognition of liver kinase B1 (LKB1) and metabolic pathways, including others, are also commented. The review serves to charter diverse treatment solutions, depending on the main altered signaling pathways, in order to have effectual immunotherapy. Tumor PDCD1 gene (encoding PD-1) has been recently described, in equilibrium with tumor PD-L1 (encoded by PDCD1LG1). Such description explains tumor hyper-progression, which has been reported in several studies, and poises the fundamental criterion that IHC PD-L1 expression as a biomarker should be revisited.
Highlights
The programmed death-1 (PD-1) pathway is a key mediator of local immunosuppression in the tumor microenvironment (TME), modulating T cell priming against tumor antigens and Cancers 2020, 12, 1475; doi:10.3390/cancers12061475 www.mdpi.com/journal/cancersCancers 2020, 12, 1475 secondary lymph nodes [1]
P53-mediates ferroptosis by repressing SLC7A11 transcription [104], indicating that p53 status is important for predicting the effect of anti-PD-1 and/or anti-PD-L1 antibodies in gauging the cystine/glutamate xCT antiporter system components, as potential therapeutic targets for SASP, DHA, or other drugs [39] (Figure 2)
Our observations in FaDu and CAL27 head and neck squamous cell carcinoma (HNSCC) cell lines are noteworthy, since DHA reduces focal adhesion kinase (FAK) phosphorylation (Tyr 397) [27]. Another intriguing point is the fact that ADRB2 signaling upregulates nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in pancreatic cancer, and increased survival was observed in patients treated with nonselective B-blockers [133]
Summary
The programmed death-1 (PD-1) pathway is a key mediator of local immunosuppression in the tumor microenvironment (TME), modulating T cell priming against tumor antigens and Cancers 2020, 12, 1475; doi:10.3390/cancers12061475 www.mdpi.com/journal/cancers. Multiple endeavors have been performed to find the best way to predict response to anti-PD-1 and anti-PD-L1 monoclonal antibodies, including the correlation with tumor mutation burden (TMB) by whole exome sequencing, considering activating mutations in receptor tyrosine kinase mutations, smoking-related mutational signature and human leukocyte antigen status in order to more accurately predict response [8]. In this complex assessment, differences in PD-L1 expression between responders and non-responders were not identified. The presence of RTK mutations (EGFR mutations) was a negative predictor of response [8]
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