Immunogenic cell death in cancer therapy: Present and emerging inducers.

Jingyi Zhou,Yingqi Hua,Yinze Chen,Hongxia Wang,Gangyang Wang,Zhengdong Cai

doi:10.1111/jcmm.14356

Abstract

In the tumour microenvironment (TME), immunogenic cell death (ICD) plays a major role in stimulating the dysfunctional antitumour immune system. Chronic exposure of damage‐associated molecular patterns (DAMPs) attracts receptors and ligands on dendritic cells (DCs) and activates immature DCs to transition to a mature phenotype, which promotes the processing of phagocytic cargo in DCs and accelerates the engulfment of antigenic components by DCs. Consequently, via antigen presentation, DCs stimulate specific T cell responses that kill more cancer cells. The induction of ICD eventually results in long‐lasting protective antitumour immunity. Through the exploration of ICD inducers, recent studies have shown that there are many novel modalities with the ability to induce immunogenic cancer cell death. In this review, we mainly discussed and summarized the emerging methods for inducing immunogenic cancer cell death. Concepts and molecular mechanisms relevant to antitumour effects of ICD are also briefly discussed.

Highlights

During the multistep progression of cancer, immune surveillance, an immune process that recognizes and destroys numerous de‐ railed cells,[1] is regarded as a regulator in the context of normal cell differentiation, cancer cell proliferation and cell death mecha‐ nisms
This study showed that high hydrostatic pressure (HHP) treatment causes apoptosis and the expression of immunogenic molecules such as HSP70, HSP90 and CRT, on the cell surface and HHP‐treated cells release High mobility group B1 (HMGB1) from the nu‐ cleus and increase extracellular adenosine triphosphate (ATP) levels
Type I immunogenic cell death (ICD) is induced through the col‐ lateral endoplasmic reticulum (ER) stress effect, indirectly inducing ICD‐associated danger signalling without triggering reactive oxygen species (ROS) production and ER stress

Summary

| INTRODUCTION

During the multistep progression of cancer, immune surveillance, an immune process that recognizes and destroys numerous de‐ railed cells,[1] is regarded as a regulator in the context of normal cell differentiation, cancer cell proliferation and cell death mecha‐ nisms. | 4857 engulfment of antigenic components by DCs.[30,31] As one of the char‐ acteristics of ICD, the expression of ecto‐HSP70 and ecto‐HSP90 on dying cell membranes has immunostimulatory properties, which lead to specific CD8+ T cell responses by driving the cross‐presentation of tumour‐derived antigenic peptides on major histocompatibility com‐ plex (MHC) class I molecules.[32,33] CRT exposure, ATP se‐ cretion and HMGB1 release by human cancer cells appear to be the gold‐standard for accurately predicting the ICD‐inducing capacity of chemotherapeutic agents Interactions between these DAMPs and phagocytosis receptors, purinergic receptors and pattern‐recognition receptors (PRRs) on the surface of innate immune cells, which act as activators that stimulate APCs to present antigens on MHC I and MHC II molecules to T cells and trigger T cell immune response against cancer‐specific antigens, subsequently elicit protective anticancer immune responses in vivo. The above discussion indicates that it is essential to understand the emerging methods of ICD induction and apply them to clinical cancer treatments

| EMERGING METHODS OF ICD INDUCTION

| CONCLUSIONS AND FURTHER PERSPECTIVES