Analysis of the PD-1 Ligands Among Gastrointestinal Cancer Patients: Focus on Cancer Immunity.

Lin Dai,Wang Li,Zilin Huang

doi:10.3389/fonc.2021.637015

Lin Dai, Wang Li + Show 1 more

Open Access

https://doi.org/10.3389/fonc.2021.637015

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Abstract

Many types of gastrointestinal cancer have shown promising outcomes after checkpoint blockade immunotherapy; however, it remains largely unclear about the expression profiles of programmed death 1 (PD-1) ligands (CD274 and PDCD1LG2) in the context of human pan-cancer. This work comprehensively analyzed the expression pattern of the PD-1 ligands and the clinical significance in the prognosis prediction among the seven types of gastrointestinal malignancies collected from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) database. Furthermore, the correlation of CD274/PDCD1LG2 with cancer immunity was also explored. The patients with liver hepatocellular carcinoma (LIHC) receiving cytokine-induced killer (CIK) cell immunotherapy at our cancer center were enrolled. CD274 and PDCD1LG2 displayed inconsistent gene expression levels among the diverse cancer cell lines. Typically, the abnormal expression level of CD274 and PDCD1LG2 was detected in both esophageal carcinoma (ESCA) and stomach adenocarcinoma (STAD), where PDCD1LG2 was related to the overall survival (OS) of the patients in ESCA (p = 0.015) and STAD (p = 0.025). High-serum CD274 and PDCD1LG2 levels predicted a worse survival in the patients with LIHC receiving CIK therapy. More importantly, the expression level of CD274 and PDCD1LG2 was significantly correlated with the degree of Estimation of STromal and Immune cells in MAlignant Tumor tissues using the Expression data (ESTIMATE). In addition, we found that CD274 and PDCD1LG2 were correlated with gene markers in tumor-infiltrating immune cells. Furthermore, the expression of CD274 and PDCD1LG2 was correlated with tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methyltransferase (DNMT) of different types of cancers. The present work comprehensively analyzed a RNA sequencing of the PD-1 ligands across the seven distinct types of gastrointestinal cancers, which provided clues for further studies in cancer immunity and development.

Highlights

Gastrointestinal malignant tumor is a leading cause of death [1]
For the seven The Cancer Genome Atlas (TCGA)-derived cancer types, we detected that esophageal carcinoma (ESCA), pancreatic adenocarcinoma (PAAD), and stomach adenocarcinoma (STAD) showed a relatively higher gene expression
The expression landscapes of CD274 and PDCD1LG2 in TCGA cohorts are presented in Figures 1B,E, respectively

Summary

Introduction

Gastrointestinal malignant tumor is a leading cause of death [1]. The development of immunotherapy using immune checkpoint inhibitors has achieved breakthroughs in treating cancers. Programmed death 1 (PD-1) and its ligands, programmed death ligand 1 (PD-L1, or CD274) and PD-L2 (PDCD1LG2), are known as an immune checkpoint axis available to the cancer cells escaping from the immune destruction of T cells [2]. PD-1 binds two ligands CD274 and PDCD1LG2 to inhibit the T-cell activation and invalidate immune surveillance. The results from experimental investigations and clinical studies showed that PD-1/PD-L1 blockers were demonstrated to be effective in gastrointestinal cancers [3, 4]. A specific gene expression of CD274/PDCD1LG2 in gastrointestinal cancers at a pan-cancer level remains largely unknown

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