Gut-Resident IL10+CX3CR1hi Macrophages Induce Tertiary Lymphoid Structures and IgA Response in Situ
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE121471 | GEO | 2020/04/17
REPOSITORIES: GEO
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Project description:Gut-Resident IL10+CX3CR1hi Macrophages Induce Tertiary Lymphoid Structures and IgA Response in Situ
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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.
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Project description:The key role of tertiary lymphoid structures in autoimmune and non-autoimmune conditions has been recently appreciated. While many of the molecular mechanisms involved in tertiary lymphoid structure formation have been identified, their cellular sources and temporal and spatial relationship remain unknown. Using single-cell RNA-sequencing, spatial transcriptomics and proteomics of minor salivary glands of patients with Sjogren’s disease and Sicca Syndrome, ex-vivo and in vivo functional studies, we construct a cellular and spatial map of key components involved in the formation and function of tertiary lymphoid structures. We confirm the presence of a fibroblast cell state and identify an undescribed pericyte/mural cell state with potential immunological functions. The identification of novel cellular properties associated with these structures and the molecular and functional interactions identified by this analysis provide key therapeutic cues for tertiary lymphoid structures associated conditions in autoimmunity and cancer.
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Project description:The key role of tertiary lymphoid structures in autoimmune and non-autoimmune conditions has been recently appreciated. While many of the molecular mechanisms involved in tertiary lymphoid structure formation have been identified, their cellular sources and temporal and spatial relationship remain unknown. Using single-cell RNA-sequencing, spatial transcriptomics and proteomics of minor salivary glands of patients with Sjogren’s disease and Sicca Syndrome, ex-vivo and in vivo functional studies, we construct a cellular and spatial map of key components involved in the formation and function of tertiary lymphoid structures. We confirm the presence of a fibroblast cell state and identify an undescribed pericyte/mural cell state with potential immunological functions. The identification of novel cellular properties associated with these structures and the molecular and functional interactions identified by this analysis provide key therapeutic cues for tertiary lymphoid structures associated conditions in autoimmunity and cancer.
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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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