Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

Abstract

Apoptotic cell death generally characterized by a morphologically homogenous entity has been considered to be essentially non-immunogenic. However, apoptotic cancer cell death, also known as type 1 programmed cell death (PCD), was recently found to be immunogenic after treatment with several chemotherapeutic agents and oncolytic viruses through the emission of various danger-associated molecular patterns (DAMPs). Extensive studies have revealed that two different types of immunogenic cell death (ICD) inducers, recently classified by their distinct actions in endoplasmic reticulum (ER) stress, can reinitiate immune responses suppressed by the tumor microenvironment. Indeed, recent clinical studies have shown that several immunotherapeutic modalities including therapeutic cancer vaccines and oncolytic viruses, but not conventional chemotherapies, culminate in beneficial outcomes, probably because of their different mechanisms of ICD induction. Furthermore, interests in PCD of cancer cells have shifted from its classical form to novel forms involving autophagic cell death (ACD), programmed necrotic cell death (necroptosis), and pyroptosis, some of which entail immunogenicity after anticancer treatments. In this review, we provide a brief outline of the well-characterized DAMPs such as calreticulin (CRT) exposure, high-mobility group protein B1 (HMGB1), and adenosine triphosphate (ATP) release, which are induced by the morphologically distinct types of cell death. In the latter part, our review focuses on how emerging oncolytic viruses induce different forms of cell death and the combinations of oncolytic virotherapies with further immunomodulation by cyclophosphamide and other immunotherapeutic modalities foster dendritic cell (DC)-mediated induction of antitumor immunity. Accordingly, it is increasingly important to fully understand how and which ICD inducers cause multimodal ICD, which should aid the design of reasonably multifaceted anticancer modalities to maximize ICD-triggered antitumor immunity and eliminate residual or metastasized tumors while sparing autoimmune diseases.

Consensus guidelines for the detection of immunogenic cell death

“…7,[121][122][123][124][125][126][127][128][129] Such signals are conveyed by damage-associated molecular patterns (DAMPs), i.e., molecules that are not accessible by the immune system in physiological conditions but are released or exposed on the outer leaflet of the plasma membrane during cytoprotective stress responses or upon cell death. 103,[130][131][132][133] Similar to their microbial counterparts, many (but not all) DAMPs exert robust immunostimulatory effects upon binding to pattern recognition receptors (PRRs) expressed by immune cells.…”

The Expression of HMGB1 on Microparticles Released during Cell Activation and Cell Death In Vitro and In Vivo

“…While HMGB1 release can occur with apoptosis, necrosis, and necroptosis and related forms of programmed necrosis (26)(27)(28)(29)(30), in vivo models to dissect these processes have not yet been extensively characterized. There is evidence, however, that the in vivo release of DNA, to which HMGB1 can be attached, occurs similarly with cell undergoing apoptosis and necrosis.…”

Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy

“…Cells dying by other cell death pathways such as necrosis/necroptosis or pyroptosis also induce cell death associated with immunogenicity. 11,12,13 In fact, immunogenicity and inflammation associated with necrosis/necroptosis or pyroptosis was discovered before apoptotic ICD was characterized. In spite of this, it is not yet completely clear to what extent the molecular nature of the danger signals, which are mainly passively exposed by necrotic dying cancer cells, overlaps with that of immunogenic apoptosis.…”