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.

Figure 1

Oncolytic virus (CVB3) infection-triggered cancer cell death induces innate immune cell-mediated antitumor immunity. Intratumoral CVB3 infection-activated natural killer (NK) cells and granulocytes with enhanced expression of CD107a, a cytolytic degranulation marker, have been found to contribute to substantial antitumor effects as evidenced by NK cell and granulocyte depletion assays. Upon CVB3 infection, tumor cells can partially induce ecto-CRT on human tumor cells during early apoptosis, whereas majority of other viruses subvert ICD by circumventing ecto-CRT induction, and followed by robust release of DAMPs, including ATP and HMGB1, during later stages of cell death, which facilitates maturation of DCs via binding to Toll-like receptor 4 (TLR4)/RAGE and P₂ × ₇R, respectively. Viral genomes and/or viral progenies also stimulate DCs for their activation. Mature DCs may then efficiently phagocytose TAAs simultaneously released from dying cells and ultimately cross-present them to CD8⁺ T cells with the support with CD4⁺ T cells to elicit substantial antitumor immunity. Although ATP secretion relies on autophagic machinery, the other forms of cancer cell death, such as autophagic cell death and necroptosis, triggered by CVB3 infection have not yet been fully investigated