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CIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE150272 | GEO | 2021/04/30

REPOSITORIES: GEO

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

Project description:Loss of major histocompatibility complex (MHC) class I and interferon-γ (IFN-γ) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor κB (NF-κB) signaling. Induction of noncanonical NF-κB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-κB signaling induces T cell-dependent immune responses, even in β2-microglobulin (β2M)-deficient tumors, demonstrating that direct CD8 T cell recognition of tumor cell-expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild-type mice, but not mice incapable of antigen-specific T cell responses, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of noncanonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.

| S-EPMC8406785 | 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 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. We characterized by single-cell RNA-Seq the transcriptional profile of immune cells infilitrating mouse pancreatic tumors treated with the IAP anatagonist LCL161.

2021-04-30 | GSE150271 | 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 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

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

| PRJNA631696 | 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

| PRJNA631699 | ENA

Distinctive Cellular and Metabolic Reprogramming in Porcine Lung Mononuclear Phagocytes Infected With Type 1 PRRSV Strains.

Project description:Porcine reproductive and respiratory syndrome (PRRS) has an extensive impact on pig production. The causative virus (PRRSV) is divided into two species, PRRSV-1 (European origin) and PRRSV-2 (North American origin). Within PRRSV-1, PRRSV-1.3 strains, such as Lena, are more pathogenic than PRRSV-1.1 strains, such as Flanders 13 (FL13). To date, the molecular interactions of PRRSV with primary lung mononuclear phagocyte (MNP) subtypes, including conventional dendritic cells types 1 (cDC1) and 2 (cDC2), monocyte-derived DCs (moDC), and pulmonary intravascular macrophages (PIM), have not been thoroughly investigated. Here, we analyze the transcriptome profiles of in vivo FL13-infected parenchymal MNP subpopulations and of in vitro FL13- and Lena-infected parenchymal MNP. The cell-specific expression profiles of in vivo sorted cells correlated with their murine counterparts (AM, cDC1, cDC2, moDC) with the exception of PIM. Both in vivo and in vitro, FL13 infection altered the expression of a low number of host genes, and in vitro infection with Lena confirmed the higher ability of this strain to modulate host response. Machine learning (ML) and gene set enrichment analysis (GSEA) unraveled additional relevant genes and pathways modulated by FL13 infection that were not identified by conventional analyses. GSEA increased the cellular pathways enriched in the FL13 data set, but ML allowed a more complete comprehension of functional profiles during FL13 in vitro infection. Data indicates that cellular reprogramming differs upon Lena and FL13 infection and that the latter might keep antiviral and inflammatory macrophage/DC functions silent. Although the slow replication kinetics of FL13 likely contribute to differences in cellular gene expression, the data suggest distinct mechanisms of interaction of the two viruses with the innate immune system during early infection.

| S-EPMC7750501 | biostudies-literature

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

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