Squamous cell lung carcinoma (SQCC) accounts for 20–30% of all non-small cell lung cancers (NSCLCs).1 With distinct clinicopathological features, such as a lack of targetable mutations, higher incidence in older individuals, and advanced or metastatic disease at diagnosis, patients with SQCC have a shorter lifespan than those with other NSCLC subtypes.2–4 Despite surgical resection, many patients with NSCLC experience relapse.5 In surgically resected NSCLC (pathological stages IA–IIB), the 5-year survival rate is approximately 40–70%, but drops to 13% and 5% for stage IIIA and IIIB disease, respectively.6
Prior to immunotherapy, the first-line treatment options for advanced SQCC were limited to platinum-doublet chemotherapy, with a median survival of 8–11 months.7 The advent of pembrolizumab, a programmed cell death protein-1 (PD-1) inhibitor, revolutionized the first-line treatment options for both patients with squamous and non-squamous NSCLC with programmed death ligand-1 (PD-L1) expression levels of ≥ 50%.8 However, only 30% of patients with advanced NSCLC exhibit high levels of PD-L1 expression and are eligible for treatment with pembrolizumab.8,9
Recently, adding pembrolizumab to chemotherapy resulted in a significant survival advantage for patients with advanced SQCC in first-line settings, regardless of PD-L1 expression.10 Although the PD-L1 tumor proportion score is currently a biomarker for first-line treatment using pembrolizumab, the predictive role of PD-L1 in combination treatment needs further validation since patients across all categories of PD-L1 expression showed improved outcomes with combination treatment. Other combination treatments with immune checkpoint inhibitors—such as ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated protein-4—and chemotherapy did not improve overall survival (OS) in patients with metastatic squamous or non-squamous NSCLC.11
Other checkpoint receptor blockers that modulate immune cell activation are currently under investigation since a significant proportion of patients do not respond to immunotherapy.12 Among checkpoint blockers, T-cell immunoglobulin and ITIM domain (TIGIT) binds to poliovirus receptor (PVR). TIGIT is enriched on T-cells, such as regulatory T-cells, type 1 regulatory T-cells, memory T-cells, exhausted CD8 + T-cells, natural killer T-cells, and natural killer cells.13,14 Mouse models have shown that TIGIT/PVR binding induces immune evasion of tumor cells, one of the key hallmarks of cancer.15,16 Levels of PVR are usually low (or PVR is not expressed) in normal tissues, but are high in tumor cells. PVR expression is associated with the invasion, migration, and proliferation of tumor cells.17 Overexpression of PVR is observed in multiple malignancies, and tumors expressing high levels of PVR are also associated with poor prognosis.18–20
Recently, several clinical trials have evaluated the efficacy of blocking the TIGIT/PVR axis in solid cancers such as NSCLC21. Tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, an anti-PD-L1 agent, showed a promising treatment response and a manageable toxicity profile in first-line NSCLC treatment. Compared to monotherapy (atezolizumab), combination therapy improved the objective response rate (31.3% vs. 16.2%) and median progression-free survival (5.4 vs. 3.6 months). These results strongly suggest that the TIGIT/PVR axis may be a clinically useful target for treating patients with NSCLC.
Despite increasing evidence of the involvement of the TIGIT/PVR axis, few studies have addressed the prognostic role of PVR.22 Therefore, we aimed to assess PVR expression in surgically resected SQCC tissues to determine its relationship with PD-L1. We evaluated the correlations of PVR and PD-L1 expression with clinicopathological factors and determined their prognostic implications for survival outcomes in SQCC.