Immunogenic Cell Death and Immunotherapy of Multiple Myeloma

Abstract

Over the past decades, immunotherapy has demonstrated a prominent clinical efficacy in a wide variety of human tumors. For many years, apoptosis has been considered a non-immunogenic or tolerogenic process whereas necrosis or necroptosis has long been acknowledged to play a key role in inflammation and immune-related processes. However, the new concept of "immunogenic cell death" (ICD) has challenged this traditional view and has granted apoptosis with immunogenic abilities. This paradigm shift offers clear implications in designing novel anti-cancer therapeutic approaches. To date, several screening studies have been carried out to discover bona fide ICD inducers and reveal the inherent capacity of a wide variety of drugs to induce cell death-associated exposure of danger signals and to bring about in vivo anti-cancer immune responses. Recent shreds of evidence place ER stress at the core of all the scenarios where ICD occur. Furthermore, ER stress and the unfolded protein response (UPR) have emerged as important targets in different human cancers. Notably, in multiple myeloma (MM), a lethal plasma cell disorder, the elevated production of immunoglobulins leaves these cells heavily reliant on the survival arm of the UPR. For that reason, drugs that disrupt ER homeostasis and engage ER stress-associated cell death, such as proteasome inhibitors, which are currently used for the treatment of MM, as well as novel ER stressors are intended to be promising therapeutic agents in MM. This not only holds true for their capacity to induce cell death, but also to their potential ability to activate the immunogenic arm of the ER stress response, with the ensuing exposure of danger signals. We provide here an overview of the up-to-date knowledge regarding the cell death mechanisms involved in situations of ER stress with a special focus on the connections with the drug-induced ER stress pathways that evoke ICD. We will also discuss how this could assist in optimizing and developing better immunotherapeutic approaches, especially in MM treatment.

Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress

“…ICD inducers promote the release or surface exposure of DAMPs, thereby providing adjuvant signals for adaptive anticancer immune responses mediated by T lymphocytes. Subsequent immune checkpoint blockade prevents T‐cell exhaustion and improves therapeutic outcome (Pfirschke et al , ; Serrano‐Del Valle et al , ). The present data could thus lead to a regain of interest for DACT, which is currently limited to some cases of pediatric sarcoma, gestational trophoblastic diseases, and metastatic testicular carcinomas, even though it has shown efficiency in pre‐clinical studies performed in other kinds of cancers (Takusagawa et al , ; Kam & Thompson, ; Cortes et al , ).…”

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…[97][98][99][100][101][102][103][104][105][106][107][108][109] Two main criteria should be met for any treatment modality to be classified as a bona fide ICD inducer. 20,110 First, ICD-eliciting agents must exhibit superior therapeutic efficacy when employed against mouse tumors growing in immunocompetent, syngeneic (as compared to immunodeficient) hosts. 19,[111][112][113] Second, cancer cells undergoing ICD must provide tumor-naïve, syngeneic hosts with immunemediated prophylactic protection against a subsequent challenge with living cancer cells of the same (but not different) type.…”

“…[132][133][134] Some ICD inducers are indeed potent at eliciting adaptive anticancer immunity even in the presence of the immunosuppressive circuitries that are established by developing tumors, and not only in tumor-naïve settings. 110,[135][136][137][138][139][140][141][142][143][144][145][146] In addition to these in vivo experiments, which obligatorily rely on rodent cancer cells established in immunocompetent, syngeneic hosts, some in vitro or ex vivo proxy methods are available to estimate the immunogenic potential of dying cancer cells (as long as all appropriate positive and negative controls are thoroughly evaluated). 12,19,77,[147][148][149][150] The main advantage of these methods is that they can be employed for both rodent and human cancer cells.…”

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

“…Radiation can induce various forms of cell death including apoptosis [10], mitotic catastrophe [11], autophagic cell death [12], necroptosis [13], and necrosis [14][15][16]. The type of cell death induced is dependent on the genetic background of cancer cells, the tumor microenvironment, and the dose of radiation applied.…”

“…Similarly, autophagic cell death, necroptosis, and necrosis release DAMPs into the intercellular space, as well as cancer-specific antigens. Both can lead to strong immunogenic responses [15,16,27]. Danger-associated molecular patterns act as immune activating signals and stimulate dendritic cells (DCs) towards a T-cell activating phenotype by binding to pattern recognition receptors [28] (Figure 1).…”