Biology subjects

Ambrosini, M.

Publications and source records attributed to Ambrosini, M..

4 recordsLinked to original sources

bioRxiv2026

Epigenetic evolution of colorectal cancer and its microenvironment reveals new vulnerabilities

Epigenetics is central to tumorigenesis, but the co-evolution of the cancer epigenome and its microenvironment is severely understudied. Here, we measure chromatin accessibility and transcriptome, at single cell resolution, of a set of normal colon, primary colorectal cancers and metastases, and identify recurrent epigenetic alterations in tumour cells. We also found that the normal epithelium adjacent to the cancer had recurrent epigenetic alterations associated with inflammatory programs that were partially shared with tumour cells. Distinct tumour-intrinsic transcription factor binding programs were associated with differential abundance of malignant stroma cell identities. We then leveraged matched patient-derived organoids, to assess the functional impact of the most recurrent epigenetic alterations on cancer cell viability, using CRISPR interference. We found a set of epigenetic-driven cancer dependencies, related to developmental reprogramming and cellular stress resilience, representing new potential therapeutic targets.

cancer biology↗

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

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↗

bioRxiv2019

Comparison of intradermal injection and epicutaneous laser microporation for anti-tumor vaccine delivery in a human skin explant model

Human skin is a prime vaccination site containing multiple antigen presenting cells (APC), including Langerhans cells (LC) and dendritic cells (DC). APC deliver antigens to lymph nodes for induction of adaptive immunity through stimulating antigen specific T- and B-cells. Since intradermal (ID) injections require specific training, easy applicable delivery systems like laser microporation are emerging. In mice, combination of laser treatment and allergen injection showed enhanced T-cell responses and skewing of B-cell responses without adjuvants. However, it remains to be elucidated whether laser microporation can alter human skin DC phenotype and function without adjuvants. In an ex-vivo human skin explant model, we compared ID injection and laser microporation as anti-tumor vaccination strategy. A melanoma specific synthetic long peptide and multivalent dendrimer with gp100 antigen were used as vaccine formulation to measure APC phenotype, emigration and ability to stimulate gp100 specific CD8+ T-cells. We show that skin APC phenotype and emigration capacity was similar after laser microporation and ID injection. However, laser microporation reduced vaccine uptake by APC, resulting in decreased induction of gp100 specific CD8+ T-cell activation. To conclude, in our human skin model ID injection remains the most potent strategy to deliver antigens to skin APC for T-cell induction. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/861930v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@5b7191org.highwire.dtl.DTLVardef@17d16fcorg.highwire.dtl.DTLVardef@1701e08org.highwire.dtl.DTLVardef@1c3ab3d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗