The Potential Role of circRNA in Tumor Immunity Regulation and Immunotherapy

Abstract

Non-coding RNAs (ncRNAs) can be divided into circular non-coding RNAs (circRNAs) and linear ncRNAs. ncRNAs exist in different cell types, including normal cells, tumor cells and immunocytes. Linear ncRNAs, such as long ncRNAs and microRNAs, have been found to play important roles in the regulation of tumor immunity and immunotherapy; however, the functions of circRNAs in tumor immunity and immunotherapy are less known. Here, we review the current status of ncRNAs in the regulation of tumor immunity and immunotherapy and emphatically discuss the potential roles of circRNAs as tumor antigens in the regulation of tumor immunity and immunotherapy.

Keywords: antitumor immunity; circular RNAs; non-coding RNAs; tumor antigen; tumor immunotherapy.

Figure 1

Current immunotherapy research. (A) CAR-T cell therapy indicates that T cells collected from cancer patients are genetically engineered to identify the tumor antigens and activate T cells to achieve the effect of antitumor immunity; (B) immune checkpoint therapy blocks programmed cell death protein 1 (PD-1) or cytotoxic T lymphocyte-associated antigen (CTLA4). PD-1 binds to PD-L1 to inhibit protein-tyrosine phosphatase-2 (SHP-2), which is involved in CTL activation. Pembrolizumab or nivolumab can block PD-1, allowing SHP-2 to strengthen the antitumor immunity. CTLA4 competes with CD28 for binding to CD80/86 to activate T cells. After blocking CTLA4 with ipilimumab, CD28 can bind to CD80/86 to help activate T cells and strengthen antitumor immunity; (C) cancer vaccine therapy includes using tumor-associated antigens (TAA) or a tumor-associated virus to activate antigen-presenting cells (APCs), such as dendritic cells (DCs), or to activate cytotoxic T cells (CTLs) to assist antitumor immunity or genetically engineering tumor cells to make them express immune stimulatory cytokines, such as GM-CSF, to stimulate anti-tumor immunity; (D) oncolytic virus therapy indicates that oncolytic viruses can kill tumor cells or enhance the identification of their presented antigens by APCs to assist with antitumor immunity.

Figure 2

Putative roles of circular RNAs (circRNAs) in antitumor immune regulation and immunotherapy. (A) circRNAs can bind to microRNAs (miRNAs) to upregulate the expression of genes associated with antitumor immunity, including PD-L1 and STAT3; (B) circRNAs can bind proteins, such as MDM2 and p53, to regulate their stability and antitumor immunity; (C) circRNAs in tumor exosomes may be transported to immunocytes as tumor antigens to activate antitumor immunity or bind to miRNAs and proteins to regulate immunocyte activity; (D) circRNAs may stabilize miRNAs in exosomes when they are transported from tumor cells to immunocytes and then help release the miRNAs into the immunocytes.