IgA transcytosis and tumor antigen recognition govern anti-tumor immunity in ovarian cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA612038 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11287527_1.fastq.gz | Fastqsanger.gz | |||
| SRR11287527_2.fastq.gz | Fastqsanger.gz | |||
| SRR11287528_1.fastq.gz | Fastqsanger.gz | |||
| SRR11287528_2.fastq.gz | Fastqsanger.gz | |||
| SRR11287529_1.fastq.gz | Fastqsanger.gz |
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Project description:Although most ovarian cancers show prognostically relevant activated T-cell infiltrates, response rates to immune checkpoint inhibitors are very modest4. Memory B-cell and plasma cell infiltrates have been associated with better outcome in ovarian cancer, but the nature and functional relevance of these responses are controversial. Using 3 independent cohorts totaling 575 high-grade serous ovarian cancer (HGSOC) patients, we show that robust humoral responses are heavily dominated by the production of polyclonal IgA, which binds to Polymeric IgA Receptors universally expressed on ovarian cancer cells. Notably, all tertiary lymphoid structures identified in ~21% of HGSOCs contain IgA-producing oligoclonal B-cells. Strikingly, tumor Bcell-derived IgAs effectively target extracellular oncogenic drivers, whereas IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and that sensitize tumor cells to T-cell cytolytic killing, hindering malignant progression. Thus, tumor antigen-specific and antigen-independent IgA responses antagonize ovarian cancer growth by governing coordinated tumor cell, T-cell and B-cell responses. These findings provides a platform for the identification of novel targets spontaneously recognized by intratumoral B-cell-derived antibodies, and suggest that immunotherapies that augment B-cell responses may be more effective than T-cell-centric approaches, particularly for malignancies resistant to checkpoint inhibitors.
2020-12-01 | PXD018079 | Pride
Project description:Most ovarian cancers are infiltrated by prognostically relevant activated T cells1-3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.
| S-EPMC7969354 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Neutrophils can efficiently trigger cytotoxicity towards tumor cells and other target cells upon engagement of the IgA receptor CD89. However, the cell-intrinsic factors that influence the induction of cell death upon exposure to neutrophil effector mechanisms in vivo remain largely unknown. To uncover genetic regulators that influence target cell sensitivity to IgA-induced neutrophil-mediated killing, we used a human CD89 (hCD89) transgenic mouse model in which IgA-mediated killing of Her2-positive CD47-deficient murine target cells is mediated by neutrophils. Using a genome-wide in vivo screening approach, we demonstrate that deletion of the gene encoding inositol-tetrakisphosphate 1 kinase, ITPK1, increases survival of target cells in anti-Her2 IgA-treated mice. Moreover, we show that this effect depends on neutrophil activity and on the ITPK1 kinase domain. Notably, ITPK1 deficiency did not measurably impact survival of IgA-opsonized target cells in in vitro systems, underscoring the importance of in vivo screening systems to uncover physiologically relevant regulators of neutrophil killing.
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Project description:Neutrophils can efficiently trigger cytotoxicity towards tumor cells and other target cells upon engagement of the IgA receptor CD89. However, the cell-intrinsic factors that influence the induction of cell death upon exposure to neutrophil effector mechanisms in vivo remain largely unknown. To uncover genetic regulators that influence target cell sensitivity to IgA-induced neutrophil-mediated killing, we used a human CD89 (hCD89) transgenic mouse model in which IgA-mediated killing of Her2-positive CD47-deficient murine target cells is mediated by neutrophils. Using a genome-wide in vivo screening approach, we demonstrate that deletion of the gene encoding inositol-tetrakisphosphate 1 kinase, ITPK1, increases survival of target cells in anti-Her2 IgA-treated mice. Moreover, we show that this effect depends on neutrophil activity and on the ITPK1 kinase domain. Notably, ITPK1 deficiency did not measurably impact survival of IgA-opsonized target cells in in vitro systems, underscoring the importance of in vivo screening systems to uncover physiologically relevant regulators of neutrophil killing.
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Project description:Neutrophils can efficiently trigger cytotoxicity towards tumor cells and other target cells upon engagement of the IgA receptor CD89. However, the cell-intrinsic factors that influence the induction of cell death upon exposure to neutrophil effector mechanisms in vivo remain largely unknown. To uncover genetic regulators that influence target cell sensitivity to IgA-induced neutrophil-mediated killing, we used a human CD89 (hCD89) transgenic mouse model in which IgA-mediated killing of Her2-positive CD47-deficient murine target cells is mediated by neutrophils. Using a genome-wide in vivo screening approach, we demonstrate that deletion of the gene encoding inositol-tetrakisphosphate 1 kinase, ITPK1, increases survival of target cells in anti-Her2 IgA-treated mice. Moreover, we show that this effect depends on neutrophil activity and on the ITPK1 kinase domain. Notably, ITPK1 deficiency did not measurably impact survival of IgA-opsonized target cells in in vitro systems, underscoring the importance of in vivo screening systems to uncover physiologically relevant regulators of neutrophil killing.
2024-10-09 | GSE273585 | GEO
Project description:Neutrophils can efficiently trigger cytotoxicity towards tumor cells and other target cells upon engagement of the IgA receptor CD89. However, the cell-intrinsic factors that influence the induction of cell death upon exposure to neutrophil effector mechanisms in vivo remain largely unknown. To uncover genetic regulators that influence target cell sensitivity to IgA-induced neutrophil-mediated killing, we used a human CD89 (hCD89) transgenic mouse model in which IgA-mediated killing of Her2-positive CD47-deficient murine target cells is mediated by neutrophils. Using a genome-wide in vivo screening approach, we demonstrate that deletion of the gene encoding inositol-tetrakisphosphate 1 kinase, ITPK1, increases survival of target cells in anti-Her2 IgA-treated mice. Moreover, we show that this effect depends on neutrophil activity and on the ITPK1 kinase domain. Notably, ITPK1 deficiency did not measurably impact survival of IgA-opsonized target cells in in vitro systems, underscoring the importance of in vivo screening systems to uncover physiologically relevant regulators of neutrophil killing.
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Project description:To compare gene expression between CD11b+ IgA and CD11b- IgA cells in the small intestine, each cell population was isolated from the murine small intestine. Similar experiment with different sample was performed as described in Gene expression on CD11b+ IgA and CD11b- IgA cells in the small intestine #02
2013-04-01 | E-GEOD-37225 | biostudies-arrayexpress
Project description:Krüppel-like factor 2 (KLF2) is a potent regulator of lymphocyte differentiation, activation and migration. However, its functional role in adaptive and humoral immunity remains elusive. Therefore, by using mice with a B cell-specific deletion of KLF2, we investigated plasma cell differentiation and antibody responses. We revealed that the deletion of KLF2 resulted in perturbed IgA plasma cell compartmentalization, characterized by the absence of IgA plasma cells in the bone marrow, their reductions in the spleen, the blood and the lamina propria of the colon and the small intestine, concomitant with their accumulation and retention in mesenteric lymph nodes and Peyer’s patches. Most intriguingly, secretory IgA in the intestinal lumen was almost absent, dimeric serum IgA was drastically reduced and antigen-specific IgA responses to soluble Salmonella flagellin were blunted in KLF2-deficient mice. Perturbance of IgA plasma cell localization was caused by deregulation of CCR9, Integrin chains αM, α4, β7, and sphingosine-1-phosphate receptors. Hence, KLF2 not only orchestrates the localization of IgA plasma cells by fine-tuning chemokine receptors and adhesion molecules but also controls IgA responses to Salmonella flagellin.
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