Inflammatory cell death induced by cytotoxic lymphocytes: a dangerous but necessary liaison

Abstract

Cytotoxic lymphocytes (CLs), and more specifically Tc and NK cells, are the main executors of cell death in the immune system, playing a key role during both immunosurveillance and immunotherapy. These cells induce regulated cell death (RCD) by different mechanisms, being granular exocytosis and expression of death ligands the most prominent and best characterised ones. Apoptosis, a traditionally considered lowinflammatory type of cell death, has been accepted for years as the paradigm of RCD induced by CLs. However, several recent studies have demonstrated that NK cells and Tc cells can also induce more inflammatory forms of cell death, namely necroptosis, pyroptosis and ferroptosis. Activation of these highly inflammatory types of cell death appears to critically contribute to the activation of a successful antitumor immune response. Additionally, the role of specific cell death pathways in immunogenic cell death is still under intense debate, especially considering the interconnections with other inflammatory forms of cell death. These evidences, together with the advent of new cancer immunotherapies, highlight the necessity to deepen our understanding of the link between the cell death triggered by CLs and inflammation. This knowledge will be instrumental to maximise the antitumor potential of immunotherapies, minimising deleterious effects associated with these treatments. In this review, we will briefly summarise the main features of apoptosis, necroptosis, pyroptosis and ferroptosis, to subsequently discuss the most recent evidences about the role of these RCD pathways during the elimination of cancer cells mediated by CLs and its modulation to increase the efficacy of cancer immunotherapy.

Necroptosis-Associated lncRNA Prognostic Model and Clustering Analysis: Prognosis Prediction and Tumor-Infiltrating Lymphocytes in Breast Cancer

“…Some studies suggest that necroptosis of tumor cells recruits TILs and enhances the immune effect of it after releasing response by promoting the release of inflammatory mediators such as calreticulin, HMGB1, ATP, IL-6, and IL-33, which strengthens the immunotherapeutic effect by converting the cold tumors to hot [ 45 ]. However, little is known regarding necroptosis induction by lymphocytes and its bearing on the response to immunotherapy [ 46 ]. Lipid oxidation function was abundant in the low-risk group, which raises the possibility that the intra-tumoral cytotoxic lymphocytes increase the level of oxidized lipids in tumor cells, resulting in necroptosis and increased response to immunotherapy.…”

All About (NK Cell-Mediated) Death in Two Acts and an Unexpected Encore: Initiation, Execution and Activation of Adaptive Immunity

“…When the ligands are bound to their receptors, DD induces receptor trimerization and recruitment of Fas-associated death domain (FADD)/caspase-8 complex, which triggers cell death ( Figure 3 ). In addition, to activate different cell death modalities, depending on the composition of the signalling complexes formed after ligand-receptor interaction, some of these receptors can activate the NF-kB pathway involved in pro-survival signalling, proliferation and/or cytokine production, depending on the composition of the signalling complexes formed after ligand-receptor interaction ( 69 – 72 ).…”

“…However, when the cleavage of RIP1 and RIP3 is prevented by caspase-8 inhibitors or by the genetic deletion of caspase-8 or FADD, Complex IIb is formed ( Figure 3 ). In Complex IIb, MLKL is phosphorylated by RIP3, oligomerising and translocating to the cell membrane, where it binds to phosphatidylinositides inducing cell membrane disruption and necroptotic cell death ( 69 , 71 , 129 , 131 ).…”

“…In this way, both TRAIL and FasL can also induce necroptosis in specific conditions, such as when caspase-8 is inhibited ( 71 ). The formation of each complex is regulated by a complex network of protein interactions from host cells and pathogens, including FLIPs and IAPs, that modulate cell outcome (survival or death) and the modality of cell death ( 69 ).…”

Harnessing the Potential of NK Cell-Based Immunotherapies against Multiple Myeloma

“…Both perforin [26] and at least granzyme A and B [27] are needed for tumor cell killing by NK cells. Granzymes enter the cytosol of the tumor target cell through the perforin pore and are able to induce several types of cell death, including apoptosis, necroptosis or pyroptosis, depending on the tumor target [28]. The presence of Fas ligand (FasL) and TNF-related apoptosis inducing ligand (TRAIL) on the surface of NK cells also provide secondary pathways through which to exercise their lytic actions [25].…”