Abstract
With the increasing oncological potential of immunotherapy, several immune checkpoint modulators are being investigated. The value of immune markers, including programmed cell death ligand-1, programmed cell death-1 (PD-1), inducible co-stimulator (ICOS), lymphocyte activation gene-3, T-cell immunoglobulin, and mucin-dominant containing-3 (TIM-3), is not well known. Using tissue microarrays of 396 patients who underwent surgery for oesophageal squamous cell carcinoma (ESCC), infiltrated T-cell subsets (CD3, CD8, and Foxp3) and checkpoint protein expression were scored. With a median follow-up of 24.8 months, CD3+ TIL subsets (50.0%) had longer median recurrence-free survival (RFS, 55.0 vs 21.4 months) and overall survival (OS, 77.7 vs 35.8 months). Patients with high ICOS expression (46.5%) had longer median RFS (53.9 vs 25.3 months) and OS (88.8 vs 36.9 months). For PD-1, RFS (hazard ratio [HR] 0.67) and OS (HR 0.66) were significantly longer in the high-expression group (45.2%). In the multivariate analysis, high TIM-3 expression (50.8%) had a significant relationship with shorter RFS (HR = 1.52) and OS (HR = 1.60). High CD3+ TIL and T-cell ICOS expression were associated with favourable prognosis, whereas high TIM-3 expression suggested a poor prognosis. Our findings may confer new insights to improve ESCC outcomes beyond the application of PD-1 blockade.
Highlights
With the increasing oncological potential of immunotherapy, several immune checkpoint modulators are being investigated
The interaction between programmed cell death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) is a common and important immune-evading mechanism in many cancer types and blocking this interaction has emerged as a breakthrough in cancer therapy[5]
Eleven cases were excluded due to incomplete staining, and 396 eligible ESCC tumour samples were assessed. They were evaluated for PD-L1 expression and CD3, CD8, Foxp[3], inducible co-stimulator (ICOS), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and mucin-dominant containing-3 (TIM-3) expression (Supplementary Fig. 1)
Summary
With the increasing oncological potential of immunotherapy, several immune checkpoint modulators are being investigated. Since late 2016, PD-1 inhibitors have been approved for melanoma, non-small cell lung cancer, renal cell carcinoma, and head and neck cancer by the U.S Food and Drug Administration; compared with old cytotoxic agents, PD-1 inhibitors have superior efficacy with an improved safety profile in various tumour types[6]. These checkpoint inhibitors have been adapted to daily clinical practice, dramatically changing malignant tumour www.nature.com/scientificreports treatment. We investigated the distribution and frequency of CD3+/CD8+ T-cells, regulatory T-cells, and other immune checkpoints, including PD-L1, PD-1, ICOS, LAG-3, and TIM-3, in surgically resected ESCC and determined their prognostic value in identifying potential therapeutic targets
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