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CIAP1/2 antagonism induces antigen-specific T cell dependent immunity

ABSTRACT: cIAP1/2 antagonism induces antigen-specific T cell dependent immunity

PROVIDER: PRJNA917692 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22961050.fastq.gz	Fastqsanger.gz
	SRR22961051.fastq.gz	Fastqsanger.gz
	SRR22961052.fastq.gz	Fastqsanger.gz
	SRR22961053.fastq.gz	Fastqsanger.gz
	SRR22961054.fastq.gz	Fastqsanger.gz

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cIAP1/2 antagonism induces antigen-specific T cell dependent immunity

2023-01-25 | GSE222095 | GEO

cIAP1/2 Antagonism Induces Antigen-Specific T Cell-Dependent Immunity.

Project description:Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types in part due to inadequate T cell priming. Naive T cells can receive costimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-κB. Antagonists of the ubiquitin ligases cellular inhibitor of apoptosis protein (cIAP)1/2, also called second mitochondria-derived activator of caspases (SMAC) mimetics, induce degradation of cIAP1/2 proteins, allowing for the accumulation of NIK and constitutive, ligand-independent activation of alternate NF-κB signaling that mimics costimulation in T cells. In tumor cells, cIAP1/2 antagonists can increase TNF production and TNF-mediated apoptosis; however, pancreatic cancer cells are resistant to cytokine-mediated apoptosis, even in the presence of cIAP1/2 antagonism. Dendritic cell activation is enhanced by cIAP1/2 antagonism in vitro, and intratumoral dendritic cells show higher expression of MHC class II in tumors from cIAP1/2 antagonism-treated mice. In this study, we use in vivo mouse models of syngeneic pancreatic cancer that generate endogenous T cell responses ranging from moderate to poor. Across multiple models, cIAP1/2 antagonism has pleiotropic beneficial effects on antitumor immunity, including direct effects on tumor-specific T cells leading to overall increased activation, increased control of tumor growth in vivo, synergy with multiple immunotherapy modalities, and immunologic memory. In contrast to checkpoint blockade, cIAP1/2 antagonism does not increase intratumoral T cell frequencies. Furthermore, we confirm our previous findings that even poorly immunogenic tumors with a paucity of T cells can experience T cell-dependent antitumor immunity, and we provide transcriptional clues into how these rare T cells coordinate downstream immune responses.

| S-EPMC10036868 | biostudies-literature

cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

Project description:Induction of non-canonical NF-kB signaling with IAP antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We now show that induction of non-canonical NF-kB signaling induces T-cell dependent immune responses even in B2M-null tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced cytokines reprogram macrophages to be tumoricidal. In wildtype mice IAP antagonism reduces tumor burden by increasing phagocytosis of tumor cells. We characterized by RNA-Seq the transcriptional profile of intratumoral phagocytes with and without treatment with the IAP antagonist LCL161.

2021-04-30 | GSE150270 | GEO

cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

Project description:Induction of non-canonical NF-kB signaling with IAP antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We show that induction of non-canonical NF-kB signaling induces T-cell dependent immune responses even in B2M-null tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced cytokines reprogram macrophages to be tumoricidal. In wildtype mice, IAP antagonism reduces tumor burden by increasing phagocytosis of tumor cells. We characterized by RNA-Seq the transcriptional response of macrophages to T-cell produced lymphotoxin (LT) in the presence or absence of the IAP antagonist LCL161.

2021-04-30 | GSE150269 | GEO

Oncolytic ORFV induces antitumor immunity

Project description:Oncolytic ORFV induces antitumor immunity

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cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

Project description:cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

| PRJNA631697 | ENA

cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

Project description:cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

| PRJNA631698 | ENA

cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

Project description:cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes