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Review
. 2020 Aug 1;9(8):1823.
doi: 10.3390/cells9081823.

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

Jenny Sprooten  1 , Pieter De Wijngaert  1 , Isaure Vanmeerbeerk  1 , Shaun Martin  2 , Peter Vangheluwe  2 , Susan Schlenner  3 , Dmitri V Krysko  4   5 , Jan B Parys  6 , Geert Bultynck  6 , Peter Vandenabeele  7   8   9 , Abhishek D Garg  1
Affiliations
Review

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

Jenny Sprooten et al. Cells. .

Abstract

Immune-checkpoint blockers (ICBs) have revolutionized oncology and firmly established the subfield of immuno-oncology. Despite this renaissance, a subset of cancer patients remain unresponsive to ICBs due to widespread immuno-resistance. To "break" cancer cell-driven immuno-resistance, researchers have long floated the idea of therapeutically facilitating the immunogenicity of cancer cells by disrupting tumor-associated immuno-tolerance via conventional anticancer therapies. It is well appreciated that anticancer therapies causing immunogenic or inflammatory cell death are best positioned to productively activate anticancer immunity. A large proportion of studies have emphasized the importance of immunogenic apoptosis (i.e., immunogenic cell death or ICD); yet, it has also emerged that necroptosis, a programmed necrotic cell death pathway, can also be immunogenic. Emergence of a proficient immune profile for necroptosis has important implications for cancer because resistance to apoptosis is one of the major hallmarks of tumors. Putative immunogenic or inflammatory characteristics driven by necroptosis can be of great impact in immuno-oncology. However, as is typical for a highly complex and multi-factorial disease like cancer, a clear cause versus consensus relationship on the immunobiology of necroptosis in cancer cells has been tough to establish. In this review, we discuss the various aspects of necroptosis immunobiology with specific focus on immuno-oncology and cancer immunotherapy.

Keywords: T cells; cytokines; damage-associated molecular patterns (DAMPs); danger signals; dendritic cells; immunogenic cell death; interferons; macrophages; patients; prognostic/predictive biomarkers.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A genetic analysis of tumor-specific genetic “selection pressures” on apoptosis- and necroptosis-relevant genes. A Genomic Identification of Significant Targets in Cancer (GISTIC) analysis of DNA deletion based on the analysis of 3131 cancer samples from 54 cancer types using the Tumorscape (www.broadinstitute.org/tumourscape) database (accessed in May 2018). GISTIC scores (X-axis) and false-discovery rate or FDR (Y-axis; Q-values with 0.25 as cut-off for significance) for each alteration are plotted. GISTIC is an algorithm that strives to characterize putative cancer-driving somatic copy-number alterations (SCNAs) by analyzing the frequency as well as amplitude of the observed genetic events (e.g., deletions) [68]. Accordingly, GISTIC score (X-axis) provides a prediction of genetic deletion events under both loci-specific selection pressure as well as background genetic (random) deletion rates (which naturally tend to be very high in cancer). However, the Q-values (Y-axis) further allow the differentiation between the above two events, such that a significantly low Q-value signifies loci-specific selection pressures whereas a high Q-value signifies random genetic deletion events at the same rate as background genetic aberrations in cancer. For further details on this analysis’s methodology, we refer the reader to the publication by Mermel et al. [68]. Of note, whereas RIPK1 is indeed a necrosome-relevant gene, its functions are not exclusive to necroptosis since it can also play differential role in apoptosis or survival.
Figure 2
Figure 2
Schematic overview of the mechanisms and cell fate decisions’ crosstalk underlying necroptosis induction. See the text for further details on the pathway. Calcium (Ca2+), cellular inhibitor of apoptosis protein 1/2 (cIAP1/2), cylindromatosis (CYLD), death receptor (DR), damage-associated molecular patterns (DAMPs), extracellular signal-regulated kinases (ERK), endosomal sorting complexes required for transport III (ESCRT-III), fas associated via death domain (FADD), FAS ligand (FASL), FLICE-like inhibitory protein (FLIPL), interferon receptor (IFNR), IκB kinase α/β (IKKα/β), c-Jun N-terminal kinase (JNK), linear ubiquitin chain assembly complex (LUBAC), mixed lineage kinase domain like pseudokinase (MLKL), NF-κB essential modulator (NEMO), nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB), receptor-interacting serine/threonine-protein kinase 1/3 (RIPK1/3), TAK-1 binding protein 1/2 (TAB1/2), transforming growth factor-β-activated kinase 1/2 (TAK), t-cell receptor (TCR), toll-like receptor (TLR), tumor necrosis factor (TNF), tumor necrosis factor receptor 1 (TNFR1), TNF receptor type1-associated death domain (TRADD), TNF receptor associated factor 2/5 (TRAF2/5), TNF-related apoptosis-inducing ligand (TRAIL), toll/il-1 receptor domain-containing adaptor inducing interferon-β (TRIF), ubiquitinated (Ub).
Figure 3
Figure 3
A schematic overview of necroptosis driven pro-tumor or anti-tumor immune responses. Necroptotic cancer cells release, damage-associated molecular patterns (DAMPs), chemokines, cytokines, and/or cancer antigens [and can also surface-expose phosphatidylserine (PtdSer)], which creates an inflammatory immune microenvironment that can either have anti-tumor or pro-tumor effects. In the former scenario, necroptotic cancer cells may attract macrophages and naïve dendritic cells (DCs), that can get activated by necroptosis-derived DAMPs/cytokines (1a). Herein, activated DCs can migrate to the lymph nodes and cross-prime naïve CD8+/CD4+ T cells for cancer antigens (1b). Upon such interactions, naïve T cells can differentiate into effector cytotoxic T cells and re-circulate out of the lymph nodes to infiltrate the tumor and kill the cancer cells. In parallel, RIPK3 can also induce the expression of cytokines that can activate natural killer T cells (NKT cells) which will also help in killing the cancer cells (1c). However, in the latter scenario, necroptotic cancer cells can also attract myeloid-derived suppressor cells (MDSC), and/or tumor-associated macrophages (TAM) which can cause tumor-associated immune suppression (2a). In parallel, cytokines released by necroptotic cancer cells can also promote angiogenesis, cancer proliferation and metastasis, combined with the release of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) thereby facilitating genomic instability (2b), and further contributing toward tumor progression (2c).
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