Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

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.

Commentary: Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

“…Response rate is low, with median progression free survival, that is generally short-lived (12). It is possible, as above described, that if tumor PD-1 is in equilibrium with tumor PD-L1, the disruption of intratumoral PD1-PD-L1 induced by monoclonal antibodies that block PD-1 (nivolumab or pembrolizumab) or PD-L1 (atezolizumab, durvalumab and avelumab) can provoke tumor hyper-progression which has been reported in several studies (13) (Figure 1). The figure summarizes the previous reports on the conflicting role that PD-1 or PD-L1 monoclonal antibodies could have in causing tumor progression.…”

“…In our opinion, in addition to assessing patients for PD-L1 expression in the tumor, the expression of PD-1 in the tumor could serve as a potential biomarker to define efficacy or tumor progression following immunotherapy with either anti-PD-1 o anti-PD-L1 monoclonal antibodies (13).…”

Tumor microenvironment subtypes and immune-related signatures for the prognosis of breast cancer

“…Herein, immune checkpoints were selected to be evaluated between these two pIRS groups. This part of results revealed that PDCD1 [24], ICAM1 [25], and GZMA [26], which were associated with proactivity of cytotoxic T lymphocytes and cancer immunity, were predictive of prolonged prognosis in low pIRS group, and VEGFA, as the leading molecule of tumor-induced angiogenesis for tumor invasion [27], exhibited an increased expression in breast cancer patients with limited survival of patients from high pIRS group.…”

Uncovering the Anti-Lung-Cancer Mechanisms of the Herbal Drug FDY2004 by Network Pharmacology

“…The estrogen pathway and its components may possess carcinogenic properties in LC and act as potential targets [ 128 – 131 ]. The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway is involved in the regulation of tumor-related immune processes, and it is a key target of cancer immunotherapy, which attempts to suppress immune escape and enhance antitumor immunity for the durable regression of malignant tumors of LC [ 132 – 134 ]. The dysfunction of genes and proteins comprising the p53 pathway, one of the common carcinogenic causes, is associated with various cancerous behaviors of LC cells, such as uncontrolled proliferation, survival, and cell cycle progression [ 61 , 63 , 135 – 143 ].…”