Biology subjects

Crozat, K.

Publications and source records attributed to Crozat, K..

4 recordsLinked to original sources

bioRxiv2020

An NF-κB/IRF1 axis programs cDC1s to drive anti-tumor immunity

Conventional type 1 dendritic cells (cDC1s) are critical for anti-tumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8+ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the anti-tumor functions of cDC1s are poorly understood. We mapped the molecular pathways regulating intra-tumoral cDC1 maturation using single cell RNA sequencing. We identified NF-{kappa}B and IFN pathways as being highly enriched in a subset of functionally mature cDC1s. The specific targeting of NF-{kappa}B or IFN pathways in cDC1s prevented the recruitment and activation of CD8+ T cells and the control of tumor growth. We identified an NF-{kappa}B-dependent IFN{gamma}-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. We used single cell transcriptomes to map the trajectory of intra-tumoral cDC1 maturation which revealed the dynamic reprogramming of tumor-infiltrating cDC1s by NF-{kappa}B and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-{kappa}B or IRF1 in cDC1s, resulting in impaired expression of IFN-{gamma}-responsive genes and consequently a failure to efficiently recruit and activate anti-tumoral CD8+ T cells. Finally, we demonstrate the relevance of these findings to cancer patients, showing that activation of the NF-{kappa}B/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-{kappa}B/IRF1 axis in cDC1s may therefore represent an important focal point for the development new diagnostic and therapeutic approaches to improve cancer immunotherapy. One Sentence SummaryNF-{kappa}B and IRF1 coordinate intra-tumoral cDC1 maturation and control of immunogenic tumor growth.

immunology↗

bioRxiv2020

cDC1 and interferons promote spontaneous CD4+ and CD8+ T cell protective responses to breast cancer

Here we show that efficient breast cancer immunosurveillance relies on cDC1, conventional CD4+ T cells, CD8+ cytotoxic T lymphocytes (CTL) and later NK/NK T cells. For this process, cDC1 were required constitutively, but especially during the T cell priming phase. In the tumor microenvironment, cDC1 interacted physically and jointly with both CD4+ T cells and tumorspecific CD8+ T cells. We found that interferon (IFN) responses were necessary for the rejection of breast cancer, including cDC1-intrinsic signaling by IFN-{gamma} and STAT1. Surprisingly, cell-intrinsic IFN-I signaling in cDC1 was not required. cDC1 and IFNs shaped the tumor immune landscape, notably by promoting CD4+ and CD8+ T cell infiltration, terminal differentiation and effector functions. XCR1, CXCL9, IL-12 and IL-15 were individually dispensable for breast cancer immunosurveillance. Consistent with our experimental results in mice, high expression in the tumor microenvironment of genes specific to cDC1, CTL, helper T cells or interferon responses are associated with a better prognosis in human breast cancer patients. Our results show that immune control of breast cancer depends on cDC1 and IFNs as previously reported for immunogenic melanoma or fibrosarcoma tumor models, but that the underlying mechanism differ. Revisiting cDC1 functions in the context of spontaneous immunity to cancer should help defining new ways to mobilize cDC1 functions to improve already existing immunotherapies for the benefits of patients. SynopsisType 1 conventional dendritic cells cross-present tumor antigens to CD8+ T cells. Understanding the regulation of their antitumor functions is important. Cell-intrinsic STAT1/IFN-{gamma} signaling licenses them for efficient CD4+ and CD8+ T cell activation during breast cancer immunosurveillance.

immunology↗

bioRxiv2020

Open Source ImmGen: network perspective on metabolic diversity among mononuclear phagocytes

We dissect metabolic variability of mononuclear phagocyte (MNP) subpopulations across different tissues through integrative analysis of three large scale datasets. Specifically, we introduce ImmGen MNP Open Source dataset that profiled 337 samples and extended previous ImmGen effort which included 202 samples of mononuclear phagocytes and their progenitors. Next, we analysed Tabula Muris Senis dataset to extract data for 51,364 myeloid cells from 18 tissues. Taken together, a compendium of data assembled in this work covers phagocytic populations found across 38 different tissues. To analyse common metabolic features, we developed novel network-based computational approach for unbiased identification of key metabolic subnetworks based on cellular transcriptional profiles in large-scale datasets. Using ImmGen MNP Open Source dataset as baseline, we define 9 metabolic subnetworks that encapsulate the metabolic differences within mononuclear phagocytes, and demonstrate that these features are robustly found across all three datasets, including lipid metabolism, cholesterol biosynthesis, glycolysis, and a set of fatty acid related metabolic pathways, as well as nucleotide and folate metabolism. We systematically define major features specific to macrophage and dendritic cell subpopulations. Among other things, we find that cholesterol synthesis appears particularly active within the migratory dendritic cells. We demonstrate that interference with this pathway through statins administration diminishes migratory capacity of the dendritic cells in vivo. This result demonstrates the power of our approach and highlights importance of metabolic diversity among mononuclear phagocytes.

immunology↗

bioRxiv2020

NK cells orchestrate splenic cDC1 migration to potentiate antiviral protective CD8+ T cell responses

A successful immune response relies on a tightly regulated delivery of the right signals to the right cells at the right time. Here we show that innate and innate-like lymphocytes use two mechanisms to orchestrate in time and space the functions of conventional type 1 dendritic cells (cDC1) in spleen. Early after murine cytomegalovirus infection, XCL1 production by lymphocytes with innate functions attracts red pulp cDC1 near IFN-{gamma}-producing NK cells, generating superclusters around infected cells in the marginal zone. There, cDC1 and NK cells physically interact reinforcing their reciprocal activation. Targeted IL-12 delivery and IL-15/IL-15R transpresentation by cDC1 trigger NK cell activation and expansion. In return, activated NK cells deliver GM-CSF to cDC1, triggering their CCR7-dependent relocalization into the T cell zone. This NK cell-dependent licensing of cDC1 accelerates the priming of virus-specific CD8+ T cells. Our findings reveal a novel mechanism through which cDC1 bridge innate and adaptive immunity.

immunology↗