Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity

Snyder, Annelise G.; Hubbard, Nicholas; Messmer, Michelle N.; Kofman, Sigal B.; Hagan, Cassidy; Orozco, Susana; Chiang, Kristy; Daniels, Brian P.; Baker, David; Oberst, Andrew

doi:10.1126/sciimmunol.aaw2004

Cited by 276 publications

(265 citation statements)

References 56 publications

(89 reference statements)

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“…Although emerging studies demonstrate that MLKL-driven necrotic cell death promotes anti-tumour immunity (Brumatti et al, 2016;Snyder et al, 2019), whether GSDME-driven pyroptosis restricts tumour growth in vivo is still unclear and remains an open question. For example, a study reported that GSDME expression suppresses melanoma cell growth a murine xenograft model, whereas other studies documented that Gsdme deficiency had no impact on tumour formation during intestinal cancer Croes et al, 2019).…”

Section: Gsdme Activation By Caspase-3 Promotes Pyroptosis In Some Bumentioning

confidence: 99%

“…In support of this, cancer cell lines that express high levels of GSDME are extremely susceptible to pyroptosis after exposure of apoptosis‐inducing therapies such as cisplatin, doxorubicin and etoposide, while the same treatment triggers apoptosis in GSDME‐deficient or low expressing cells (Wang et al , ). Although emerging studies demonstrate that MLKL‐driven necrotic cell death promotes anti‐tumour immunity (Brumatti et al , ; Snyder et al , ), whether GSDME‐driven pyroptosis restricts tumour growth in vivo is still unclear and remains an open question. For example, a study reported that GSDME expression suppresses melanoma cell growth a murine xenograft model, whereas other studies documented that Gsdme deficiency had no impact on tumour formation during intestinal cancer (Zhou et al , ; Croes et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis

2019

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Programmed cell death is a key mechanism involved in several biological processes ranging from development and homeostasis to immunity, where it promotes the removal of stressed, damaged, malignant or infected cells. Abnormalities in the pathways leading to initiation of cell death or removal of dead cells are consequently associated with a range of human diseases including infections, autoinflammatory disease, neurodegenerative disease and cancer. Apoptosis, pyroptosis and NETosis are three well-studied modes of cell death that were traditionally believed to be independent of one another, but emerging evidence indicates that there is extensive cross-talk between them, and that all three pathways can converge onto the activation of the same cell death effector-the pore-forming protein Gasdermin D (GSDMD). In this review, we highlight recent advances in gasdermin research, with a particular focus on the role of gasdermins in pyroptosis, NETosis and apoptosis, as well as cell type-specific consequences of gasdermin activation. In addition, we discuss controversies surrounding a related gasdermin family protein, Gasdermin E (GSDME), in mediating pyroptosis and secondary necrosis following apoptosis, chemotherapy and inflammasome activation.Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535: 111 -116

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Section: Gsdme Activation By Caspase-3 Promotes Pyroptosis In Some Bumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis

2019

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“…Then, DCs acquire high capability to migrate, to phagocytose dying cells, to process more efficiently caspase-cleaved cellular proteins (i.e., NM-neoAgs), and to cross-prime CD8 + T cells that can provide tumor control 35,38,41,42 , on the one hand, and immunopathology in various forms of chronic inflammatory diseases, on the other hand 37,[43][44][45][46][47][48] . In addition, several studies found that ICD synergizes with ICB therapy to further improve T cell responses against different tumors, proposing hence the hypothesis that ICD converts tumor cells into endogenous vaccine and boosts the ICB effects [49][50][51][52][53][54] . However, despite the large body of evidences on how ICD occurs, few evidences have been reported about the nature of antigens becoming immunogenic upon ICD 41,42 .…”

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confidence: 99%

Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens

et al. 2020

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Here, we developed an unbiased, functional target-discovery platform to identify immunogenic proteins from primary non-small cell lung cancer (NSCLC) cells that had been induced to apoptosis by cisplatin (CDDP) treatment in vitro, as compared with their live counterparts. Among the multitude of proteins identified, some of them were represented as fragmented proteins in apoptotic tumor cells, and acted as non-mutated neoantigens (NM-neoAgs). Indeed, only the fragmented proteins elicited effective multi-specific CD4 + and CD8 + T cell responses, upon a chemotherapy protocol including CDDP. Importantly, these responses further increased upon anti-PD-1 therapy, and correlated with patients' survival and decreased PD-1 expression. Cross-presentation assays showed that NM-neoAgs were unveiled in apoptotic tumor cells as the result of caspase-dependent proteolytic activity of cellular proteins. Our study demonstrates that apoptotic tumor cells generate a repertoire of immunogenic NM-neoAgs that could be potentially used for developing effective T cell-based immunotherapy across multiple cancer patients.

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“…We then examined the endogenous OVA-specific CD8 + T cell response using MHC-I peptide tetramers of SIINFEKL, referred hereafter as Tetramer (Snyder et al, 2019; Yatim et al, 2015). Tumors from Cd11c-Cre Rubcn flox/flox mice contained significantly more Tetramer + CD8 + T cells, indicating that Rubcn -deficient DCs are more efficient at cross-presentation of tumor-derived antigens (Figure 4H).…”

Section: Resultsmentioning

confidence: 99%

Non-canonical autophagy in dendritic cells restricts cross-presentation and anti-tumor immunity

Zhao

et al. 2019

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41Major Histocompatibility Complex I (MHC-I) molecules classically present peptides derived from 42 endogenous antigens, but exogenous antigens can also gain access to the MHC-I machinery in 43 dendritic cells (DCs), which can activate antigen-specific CD8 + T cells. This process, termed 44 cross-presentation, can be triggered by the uptake of dying autologous cells, including tumor cells, 45by DCs. The molecular mechanisms that underlie efficient cross-presentation remain largely 46 uncharacterized, and an improved understanding of these mechanisms might reveal novel 47 strategies for anti-tumor therapies. Rubicon (RUBCN) is a molecule required for LC3-associated 48 phagocytosis (LAP), but dispensable for canonical autophagy, and mice lacking this protein 49 develop an autoimmune inflammatory pathology with age. Here, we demonstrate that Rubcn-50 deficient DCs have increased retention of engulfed cellular cargo in immature phagosomes 51 resulting in increased phagosome-to-cytosol escape and antigen access to proteasome-mediated 52 degradation. As a result, mice selectively lacking Rubcn in DCs mount stronger tumor antigen-53 specific CD8 + T cell responses and exhibit decreased tumor burden compared to wild type 54 littermates. These findings identify LAP as a key regulator of cross-presentation and suggest that 55 targeting RUBCN might represent a novel strategy for anti-tumor therapy.The ability of the immune system to distinguish between self and non-self is integral to maintaining 75 homeostasis and eradicating exogenous threats. Antigen-presenting cells (APCs), specifically 76 DCs, educate the host's adaptive immune response in a controlled and antigen-specific manner. 77CD8 + T cells are activated by peptides generated from intracellular antigens and presented in the 78 context of MHC-I. Peptides derived from healthy self-antigens presented to CD8 + T cells in the 79 periphery elicit a minimal or absent response, as CD8 + T cells expressing T cell receptors (TCRs) 80 that recognize self-antigens undergo negative selection in the thymus prior to their population of 81 the periphery (Rock et al., 2016). However, when cells are infected by virus or are transformed 82 by an oncogene, they can produce proteins that are not considered self, such as virus-encoded 83 proteins, and the presentation of these aberrant antigens via MHC-I activates a robust CD8 + T 84 cell response (Hansen and Bouvier, 2009). Therefore, the MHC-I pathway represents an 85 evolutionarily conserved mechanism that serves as a quality control mechanism for endogenous 86 proteins and viral defense (Kaufman, 2018). 88As the activation of CD8 + T cells is largely limited to their localization within secondary lymphoid 89 tissues, they must rely on the migration of patrolling APCs to deliver antigens to them (Hansen 90 and Bouvier, 2009). Classically, exogenous antigens are sensed as foreign, phagocytosed, 91 processed by the endosomal-lysosomal network, and loaded onto MHC-II molecules to stimulate 92 antigen-specific activation of CD4 + T cel...

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Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity

Cited by 276 publications

References 56 publications

Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis

Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis

Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens

Non-canonical autophagy in dendritic cells restricts cross-presentation and anti-tumor immunity

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