The novel immune landscape of immune‐checkpoint blockade in EBV‐associated malignancies

Abstract

The Epstein–Barr virus (EBV) is a ubiquitous gamma‐herpesvirus and a class 1 carcinogen that is closely associated with a series of malignant lymphomas and epithelial cell carcinomas. Although these EBV‐related cancers may exhibit different features in clinical symptoms and anatomical sites, they all have a characteristic immune‐suppressed tumor immune microenvironment (TIME) that is tightly correlated with an abundance of tumor‐infiltrating lymphocytes (TILs) that primarily result from the EBV infection. Overwhelming evidence indicates that an upregulation of immune‐checkpoint molecules is a powerful strategy employed by the EBV to escape immune surveillance. While previous studies have mainly focused on the therapeutic effects of PD‐1 and CTLA‐4 blockades in treating EBV‐associated tumors, several novel inhibitory receptors (e.g., CD47, LAG‐3, TIM‐3, VISTA, and DDR1) have recently been identified as potential targets for treating EBV‐associated malignancies (EBVaMs). This review retrospectively summarizes the biological mechanisms used for immune checkpoint evasion in EBV‐associated tumors. Its purpose is to update our current knowledge concerning the underlying mechanisms by which an immune checkpoint blockade triggers host antitumor immunity against EBVaMs. Additionally, this review may help investigators to more fully understand the correlation between EBV infection and tumor development and subsequently develop novel therapeutic strategies.