Ruan FV Medrano

Washington University in St. Louis

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Bryan E. Strauss

Icahn School of Medicine at Mount Sinai

Aline Hunger

Instituto do Câncer do Estado de São Paulo

Renata de Freitas Saito

Universidade de São Paulo

Robert D. Schreiber

Washington University in St. Louis

Silvina Odete Bustos

Universidade de São Paulo

Paulo Roberto Del Valle

Sylvester Comprehensive Cancer Center

Maxim N. Artyomov

Washington University in St. Louis

Vladimir Sukhov

Washington University in St. Louis

Daniel G. Ferrari

Universidade Presbiteriana Mackenzie

Christian Merkel

Otto-von-Guericke University Magdeburg

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Universidade de São Paulo

Instituto do Câncer do Estado de São Paulo

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Washington University in St. Louis

Universidade Federal de São Paulo

Instituto do Coração

ITMO University

Jewish Hospital

Barnes-Jewish Hospital

Museum für Naturkunde

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Reestablishment of p53/Arf and interferon-β pathways mediated by a novel adenoviral vector potentiates antiviral response and immunogenic cell death

Cell Death Discovery (2017)

Aline Hunger Ruan FV Medrano Daniela B. Zanatta Paulo Roberto Del Valle Christian Merkel

Late stage melanoma continues to be quite difficult to treat and new therapeutic approaches are needed. Since these tumors often retain wild-type p53 and have a strong immunogenic potential, we developed a gene transfer approach which targets these characteristics. Previously, we have shown that combined gene transfer of p19Arf and interferon-beta (IFNβ) results in higher levels of cell death and superior immune-mediated antitumor protection. However, these experiments were performed using B16 cells (p53wt) with forced expression of the adenovirus receptor and also the mechanism of death was largely unexplored. Here we take advantage of a novel adenoviral vector (AdRGD-PG), presenting an RGD-modified fiber as well as a p53-responsive promoter, in order to investigate further potential benefits and cell death mechanisms involved with the combined transfer of the p19Arf and IFNβ genes to the parental B16 cell line. Simultaneous p19Arf and IFNβ gene transfer is more effective for the induction of cell death than single gene treatment and we revealed that p19Arf can sensitize cells to the bystander effect mediated by secreted IFNβ. Strikingly, the levels of cell death induced upon activating the p53/p19Arf and interferon pathways were higher in the presence of the AdRGD-PG vectors as compared to approaches using pharmacological mimetics and this was accompanied by the upregulation of antiviral response genes. Only combined gene transfer conferred immunogenic cell death revealed by the detection of key markers both in vitro and in vivo. Finally, whole-genome transcriptome analysis revealed unique expression profiles depending on gene function, including immune activation, response to virus and p53 signaling. In this way, cooperation of p19Arf and IFNβ activates the p53 pathway in the presence of an antiviral response elicited by IFNβ, culminating in immunogenic cell death.

Immunogenic cell death

Bystander effect

10.1038/cddiscovery.2017.17

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Citations (25)

Harnessing combined p19Arf and interferon-beta gene transfer as an inducer of immunogenic cell death and mediator of cancer immunotherapy

Cell Death and Disease (2017)

Aline Hunger Ruan FV Medrano Bryan E. Strauss

Harnessing combined p19Arf and interferon-beta gene transfer as an inducer of immunogenic cell death and mediator of cancer immunotherapy

Mediator

Inducer

Immunogenic cell death

Cancer Immunotherapy

BETA (programming language)

Gene transfer

10.1038/cddis.2017.201

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Citations (13)

Abstract B048: Spatiotemporal analysis during tumor rejection reveals coordinated cellular dynamics underlying successful immune-checkpoint therapy

Cancer Immunology Research (2025)

Ruan FV Medrano Vladimir Sukhov Maxim N. Artyomov Robert D. Schreiber

Abstract There is a growing appreciation for the role that the spatial organization of immune cells within the tumor microenvironment (TME) plays in shaping cellular function and response to therapy. However, the majority of studies have been limited to analyzing immune responses at a single time point, and so, little is known about the spatiotemporal changes that underlie successful tumor rejection after cancer immunotherapy. In this study, we used the CODEX multiplex imaging system with a 32-plex antibody panel to longitudinally characterize the spatial changes in the lymphoid and myeloid cell populations that were previously identified by scRNA-Seq and CyTOF to be associated with complete tumor rejection in mice treated with the combination of α-PD-1 and α-CTLA-4 (combo ICT) in our well-characterized mouse T3 MCA sarcoma model. T3 tumor-bearing mice were treated with control antibody or combo ICT, tumors were harvested at multiple time points (day 7, 9, 10, 11 and 13), fresh frozen, sectioned, and subjected to CODEX multiplex imaging. A total of 42 tumors were imaged with the full range of the tumor-immune boundary. A hierarchical cell clustering approach developed in-house was used to profile 13,051,156 cells resulting in the identification of 13 distinct cell types. Our results show that after ICT the decrease in T3 cells in the tumor tissue starts on day 10 and culminates in the complete elimination of tumor cells by day 13. This immune-mediated response is driven by an increase in CD4+ T cells, which allows them to more frequently co-localize with CD8+ T cells and type 1 conventional dendritic cells (cDC1), forming three-cell clusters with increased cell contacts. This change in cell-to-cell interactions is followed by a broader reorganization of the TME as noted by the expansion of a lymphoid-rich cellular neighborhood (CN) that harbors the majority of CD4+ and CD8+ T cells. Interestingly, this CN becomes a hub for T cell effector functions, characterized by an enrichment of GZM-B+ and KI67+ T cells, and exhibits spatial dynamics throughout tumor regression. While both GZM-B+ and KI67+ T cells are observed in proximity to blood vessels on days 7 and 9, they begin to spatially separate into distinct regions after day 10, indicating that cytotoxic T cells move towards areas with tumor cells, while proliferating T cells are more frequently observed at the periphery. This dynamic behavior was further confirmed by assessing the communication rules between CNs, which showed that the lymphoid-rich CN acts by eliminating layers of tumor cells at the tumor boundary and by modulating nearby myeloid populations. Additionally, integration of CODEX dataset with scRNA-seq revealed CD4+ T cells produce Interferon-gamma and a change in the molecular chemotactic pathways orchestrating lymphoid and myeloid communication. Overall, this study provides a detailed spatial view of the cellular events that result in successful ICT and allows us to propose a computational model of the actions of T cells in coordinating the antitumor response after α-CTLA-4/α-PD1. Citation Format: Ruan FV Medrano, Vladimir Sukhov, Maxim Artyomov, Robert Schreiber. Spatiotemporal analysis during tumor rejection reveals coordinated cellular dynamics underlying successful immune-checkpoint therapy [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B048.

Immune checkpoint

Dynamics

10.1158/2326-6074.io2025-b048

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