Immunogenic cell death

Abstract

Currently, it is widely acknowledged that a proactive anticancer immunosurveillance mechanism takes part in the rejection of neoplastic lesions before they progress towards a benign or malignant tumour. However in cases of very aggressive neoplastic lesions consisting of cells with high mutational diversity, cancer cell variants might be formed that are capable of evading host defence systems against uncontrolled proliferation and anticancer immunosurveillance. This is mainly accomplished through the exhibition of low immunogenicity, which is a particularly important stumbling block in the revival of long-lasting as well as stable anticancer immunity. Recently, it has emerged emphatically that inciting a cancer cell death routine, associated with the activation of danger signalling pathways evoking emission of damage-associated molecular patterns (DAMPs), markedly increases the immunogenicity of dying cancer cells. This cell death pathway has been termed "immunogenic cell death" (ICD). In the present review we introduce this concept and discuss its characteristics in detail. We also discuss in detail the various molecular, immunological and operational determinants of ICD. KEY WORDS: immunogenicity, immunogenic cell death, cancer, danger signals, antigen, damage-associated molecular patterns, danger signalling, ER stress, photodynamic therapy (PDT), chemotherapy Immunogenic cell death: the conceptMost newly formed neoplastic lesions in our body are readily rejected by the host defence system. It is now widely acknowledged that a proactive anticancer immunosurveillance mechanism takes part in rejection of neoplastic lesions before they progress towards a benign or malignant tumour (Dunn et al., 2002, Senovilla et al., 2012. However in cases of very aggressive neoplastic lesions consisting of cells with high mutational diversity; cancer cell variants might be formed that are capable of evading host defence systems against uncontrolled proliferation and anticancer immunosurveillance (Dunn et al., 2002, Zitvogel et al., 2006. In such a scenario, the host immune system might start acting as a "natural selection force" by performing cancer immunoediting, which might lead to the formation of cancer cells that are highly immunoevasive and capable of resisting antitumour immunity (Dunn et al., 2002). Overall resistance against the host anticancer immunosurveillance and antitumour immunity is achieved by various mechanisms including, acquaintance of low immunogenicity, ability to induce immunotolerance or active immunosuppression, and ability to resist immune cell-mediated lysis (Dunn et al., 2002, Garg et al., 2013b, Zitvogel et al., 2006. Here, the exhibition of low immunogenicity is a particularly important stumbling block in the revival Int. J. Dev. Biol. 59: 131-140 (2015) doi: 10.1387/ijdb.150061pa Abbreviations used in this paper: ATP, adenosine triphosphate; CD, cluster of differentiation; CAAs, cancer associated antigens; CRT, calreticulin; DAMP, damageassociated molecular pattern; DC, dendritic cell; ...

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

“…80 Of note, 'eat me' signals alone are not exclusive immunological determinants as their exposure is invariably accompanied by the emission of other signals (e.g., DAMPs or immunosuppressive cytokines/chemokines). 3,19,53 Thus, APC's commitment to tolerogenicity or immunogenicity is regulated by a complex program integrating a variety of signals ( Figure 1). …”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…1 Since then, considerable efforts have been dedicated to the elucidation of the molecular and cellular mechanisms underlying immunogenic cell death (ICD), defined as a functionally distinct form of regulated cell death that facilitates (instead of suppressing) an adaptive immune response specific for dead cell-derived antigens. [1][2][3][4][5][6][7] Based on the available data, it is clear that ICD can facilitate T cell responses against a wide-spectrum of differentiation, over-expressed, and mutated tumor-associated antigens (TAAs). [1][2][3][4][8][9][10][11][12][13] However, the predominance of a fraction of TAA-specific T cells in driving ICD-based immunity might be regulated by: (1) the spatiotemporal expression patterns of specific TAAs within a tumor, [14][15][16][17][18][19][20] (2) the overall coverage of various TAAs by central or peripheral tolerance, [21][22][23] (3) the overall avidity of the T cell receptor (TCR) for specific TAA, [24][25][26][27][28][29][30][31][32] and (4) the general cellular and metabolic health of effector or memory T cell fractions.…”

“…136,147,150,151 Additional details about ICD-associated signaling pathways and resistance mechanisms can be found in various publications from us and others. [2][3][4]7,40,[152][153][154][155] Of note, only a limited number of cell death inducers can elicit bona fide ICD, and this capacity cannot be predicted on the basis of structural or functional similarities. Thus, while cisplatin and oxaliplatin both induce RCD at least in part by forming interand intra-strand DNA adducts, 156 only the latter induces ICD.…”

Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients

“…[1][2][3][4] One of the mechanisms whereby neoplastic cells succumbing to specific treatments can activate the immune system is commonly referred to as "immunogenic cell death" (ICD). [5][6][7] Thus, malignant cells exposed to some chemotherapeutic agents like anthracyclines, oxaliplatin and bortezomib, as well as to fractionated radiation therapy or high hydrostatic pressures, succumb as they expose (on their surface) or release (in the extracellular milieu) a set of molecules that alert the immune system of incipient danger. [8][9][10][11] Importantly, the emission of such danger signals, which altogether are known as damage-associated molecular patterns (DAMPs), mechanistically relies on the activation of adaptive stress responses in dying cells, and hence, can be pharmacologically modulated.…”