Biology subjects

Gorvel, L.

Publications and source records attributed to Gorvel, L..

8 recordsLinked to original sources

bioRxiv2026

PVR and Nectin-2 blockade trigger macrophage anti-tumor functions, promote immune cell recruitment and prevent cervical tumor growth.

Despite vaccination, cervical tumors remain a health issue and require treatment improvement. In 2023, Pembrolizumab, an anti-PD-1 immune checkpoint blockade (ICB), was introduced in the case of advanced or metastatic cervical tumors. This treatment significantly increased progression free survival from 20% to 50%. However, some patients remain resistant to anti-PD-1 treatment, which calls for new targets. In our study, we highlighted poliovirus receptor (PVR) and Nectin-2 as potential ICB targets. Indeed, PVR and Nectin-2 are TIGIT ligands, an immunomodulatory checkpoint expressed by regulatory T cells or exhausted T cells. The binding of PVR or Nectin-2 to TIGIT maintains the immunosuppressive signal in the immune cells allowing tumor progression. Furthermore, we observed that PVR and Nectin-2 were highly expressed on tumor cells and tumor associated macrophages (TAMs) accross the different histological subsets of cervical tumors. Therefore, we hypothesized that using anti-PVR and anti-Nectin-2 anti-bodies would lift immunosuppression in cervical tumors. To that end, we used CyTOF to asses precise immunophenotyping of the targets ex vivo, high throughput confocal microscopy to assess phagocytosis, monocyte derived macrophages (MDM) coupled with 3D cell culture models to assess the impact of our treatment on MDM and TAM repolarization and tumor growth. We could demonstrate that our treatment repolarized macrophages towards an inflammatory profile and that this was followed by a reactivation of macrophage cytotoxic function such as phagocytosis. We also demonstrated that anti-PVR and Nectin-2 treatment allowed the control of tumor growth in 2D and 3D cell culture models. We could also develop a pre-clinical model of autologous cell culture from cervical cancer patients. Using the MIVO technology, which combine organotypic culture and fluidics, we could assess peripheral blood mononuclear cells recruitment towards tumor cells in the presence or absence of anti-PVR and anti-Nectin-2. In conclusion we could demonstrate that targeting macrophages via the PVR/Nectin-2 couple reactivates cervical tumor growth control and improves immune cell recruitment.

immunology↗

bioRxiv2025

CAR T cells targeting Nectin-4 safely overcome resistance to anti-Nectin-4 antibody-drug conjugate in solid tumors

Chimeric antigen receptor T (CAR T) cells represent a promising therapeutic option for a variety of cancers, including solid tumors. Nectin-4 is a cell adhesion molecule expressed at different levels in many solid tumors, including breast and urothelial carcinoma (UC). Enfortumab vedotin (EV), an antibody-drug conjugate (ADC) against Nectin-4, has significantly improved survival in patients with metastatic UC. Skin adverse reactions are frequently observed due to Nectin-4 expression in the epidermis. Here, we developed second-generation CAR T cells against Nectin-4 (N4CART) with a scFv that does not recognize human Nectin-4 expressed in skin keratinocytes. To study the effects of N4CART cell therapy, we used preclinical models of cell-derived xenografts (CDX) and patient-derived xenograft (PDX) of breast cancer expressing moderate to high levels of Nectin-4. We showed a marked efficacy with induction of remissions. Interestingly, N4CART cells kill Nectin-4-positive breast, urothelial and colon tumor cells, which are resistant to EV. Thus, N4CART cells represent a valuable and safe therapy for the treatment of patients with Nectin-4 expressing tumors, including those that are resistant to EV. Finally, baboon-envelope pseudotyped lentiviral vectors (LV) outperformed VSVG-LVs for Nectin-4 CAR expressing in {beta} T cells resulting in an efficient anti-tumoral response in PDX mice.

immunology↗

bioRxiv2025

Build heatmaps of cell frequencies and marker intensities for correct interpretations

High-content cytometry is an important technique in clinical research, producing data that is rich and complex to analyze. The resulting clusters of cells must be profiled to determine their role and function, and analyzed to identify changes in cell frequency or marker intensity. The heat map is the most suitable tool for presenting this information in a synthetic way. However, its construction must be adapted to the information and the objective. Here we describe the step-by-step construction of heat maps of marker intensity and cell frequency using Excel, Phantasus or R, including the conversion of numbers to colors and the organization of rows and columns. Researchers who master these steps will be able to correctly interpret heat maps and derive the most benefit from high-content cytometry.

bioinformatics↗

bioRxiv2024

SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria

Plasmacytoid dendritic cells (pDC), professional type I interferon (IFN) producing cells, have been implicated in host responses against bacterial infections. However, their role in host defense is debated and the operating molecular mechanisms are unknown. Certain Signaling Lymphocyte Activation Molecule Family (SLAMF) members act as microbial sensors and modulate immune functions in response to infection. Here by analyzing multiple human blood transcriptomic datasets, we report the involvement of SLAMF7 and SLAMF8 in many infectious diseases, with elevated levels associated with type I IFN responses in salmonellosis and brucellosis patients. We further identify SLAMF7 and SLAMF8 as key regulators of human pDC function. Silencing of these receptors hinders pDC maturation and abrogates cytokine production during infection with acute (Salmonella) or chronic (Brucella) inflammation-inducing bacteria. Mechanistically, we show that SLAMF7 and SLAMF8 signal through NF-{kappa}B, IRF7 and STAT-1, and limit mitochondrial ROS accumulation upon Salmonella infection. This SLAMF7/8-dependent control of mitochondrial ROS levels favors bacterial persistence and NF-{kappa}B activation. Overall, our results unravel essential shared roles of SLAMF7 and SLAMF8 in finely tuning human pDC responses to intracellular bacterial infections with high diagnosis and therapeutic perspectives.

immunology↗

bioRxiv2023

Tertiary lymphoid structures are associated with enhanced macrophage and dendritic cell activation and proximity to CD8+ T cells, which better predict the clinical outcome of cervical cancer patients

BackgroundCervical tumors are usually treated using surgery, chemotherapy, and radiotherapy, and would benefit from immunotherapies. However, the immune microenvironment in cervical cancer remains poorly described. Tertiary lymphoid structures (TLS) were recently described as markers for better immunotherapy response and overall better prognosis in cancer patients. MethodsWe integratedly evaluated the cervical tumor immune microenvironment, and specifically TLS importance, using combined high-throughput phenotyping, soluble factor dosage, spatial interaction analyses, and statistical analyses. ResultsWe demonstrate that TLS presence is associated with a more inflammatory soluble microenvironment, with the presence of B cells as well as more activated macrophages and dendritic cells (DCs). Furthermore, this myeloid cell activation is associated with expression of immune checkpoints, such as PD-L1 and CD40, and close proximity of activated conventional DC2 to CD8+ T cells, therefore indicating better immune interactions and tumor control. Finally, we associate TLS presence, greater B cell density, and activated DC density to improved progression-free survival, and present it as an additional prognostic marker. ConclusionTo conclude, our results provide an exhaustive depiction of the cervical tumor immune microenvironment where TLS presence marks cell activation and immunotherapy target expression. These findings provide predictive clues for patient response to targeted immunotherapies. SignificanceTLS maturation stratifies cervical cancer patients and associates with improved prognosis. TLS associate with the expression of immune checkpoints, notably in the macrophage compartment, which may represent a new therapeutic strategy.

immunology↗

bioRxiv2023

Targeting BTN2A1 enhances Vγ9Vδ2 T cell effector functions and triggers tumor cells pyroptosis

V{gamma}9V{delta}2 T cells are potent but elusive cytotoxic effectors. Means to stimulate their function could lead to powerful new cancer immunotherapies. BTN2A1, a surface protein has recently been shown to bind the V{gamma}9 chain of the {gamma}{delta} TCR but its precise role in modulating V{gamma}9V{delta}2 T cells functions remains unknown. Here we show that 107G3B5, a monoclonal anti-BTN2A1 agonist antibody, significantly enhances V{gamma}9V{delta}2 T cell functions against hematological or solid cell lines and against primary cells from adult acute lymphoblastic leukemia patients. New computer vision strategies applied to holotomographic microscopy videos show that 107G3B5 enhances the interaction between V{gamma}9V{delta}2 T cells and target cells in a quantitative and qualitative manner. In addition, we provide evidence that V{gamma}9V{delta}2 T cells activated by 107G3B5 induce caspase 3/7 activation in tumor cells, thereby triggering their death by pyroptosis. We thus demonstrate that targeting BTN2A1 with 107G3B5 enhances the V{gamma}9V{delta}2 T cell antitumor response by triggering the pyroptosis-induced immunogenic cell death.

cancer biology↗

bioRxiv2022

Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors

BackgroundTNFRF-14/HVEM is the ligand for BTLA and CD160 negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis. MethodsWe developed C57BL/6 mouse models co-expressing human huBTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands. ResultsHere, we show that the anti-HVEM18-10 mAb increases primary human {beta}-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cells in vitro (TRANS-activity). Anti-HVEM18-10 synergizes with anti-PD-L1 mAb to activate T cells in the presence of PDL-1 positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1 negative cells. In order to better understand HVEM18-10 effect in vivo and especially disentangle its CIS and TRANS effects, we developed a knock-in (KI) mouse model expressing human BTLA (huBTLA+/+) and a KI mouse model expressing both human BTLA and human HVEM (huBTLA+/+ /huHVEM+/+ (DKI)). In vivo pre-clinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM+ tumor growth. In the DKI model, anti-HVEM 18-10 treatment induces a decrease of exhausted CD8+ T cells and regulatory T cells and an increase of Effector memory CD4+ T cells within the tumor. Interestingly, mice which completely rejected tumors ({+/-} 20%) did not develop tumors upon re-challenge in both settings, therefore showing a marked T cell-memory phenotype effect. ConclusionsAltogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (anti-PD1/anti-PDL-1/anti-CTLA-4).

immunology↗

bioRxiv2022

Vγ9Vδ2 T cells are potent inhibitors of SARS-CoV-2 replication and exert effector phenotypes in COVID-19 patients

V{gamma}9V{delta}2 T cells play a key role in the innate immune response to viral infections, including SARS-CoV-1 and 2, and are activated through butyrophilin (BTN)-3A. Here, the objectives were to: 1) characterize the effects of SARS-CoV-2 infection on the number, phenotype, and activation of V{gamma}9V{delta}2 T cells in infected patients, and 2) assess the effects of in vitro SARS-CoV-2 infection on the expression of BTN3A and its impact on the activation and response of V{gamma}9V{delta}2 T cells to an anti-BTN3A antibody. Blood V{gamma}9V{delta}2 T cells decreased in clinically mild SARS-CoV-2 infections compared to healthy volunteers (HV). This decrease was maintained up to 28 days and in the recovery period. Terminally differentiated V{gamma}9V{delta}2 T cells tend to be enriched on the day of diagnosis, 28 days after and during the recovery period compared to HV. Furthermore, these cells showed cytotoxic and inflammatory activities as shown by TNF, IFN{gamma} and CD107a/b increase following anti-BTN3A activation. Moreover, BTN3A upregulation and V{gamma}9V{delta}2 T cell infiltration were observed in a lung biopsy from a fatal SARS-CoV-2 infection, as compared to HV. In vitro, SARS-CoV-2 infection significantly increased BTN3A expression in macrophages and lung cell lines. The activation via BTN3A enhanced the anti-SARS-CoV-2 V{gamma}9V{delta}2 T cells cytotoxicity and IFN-{gamma} and TNF in SARS-CoV-2 infected patient. Increasing concentrations of anti-BTN3A were accompanied by an inhibition of viral replication. Altogether, these data suggest that V{gamma}9V{delta}2 T cells are important in the immune response against SARS-CoV-2 infection and that activation by an anti-BTN3A antibody may enhance their response. KEY POINTSO_LISARS-CoV-2 mediates upregulation of the key receptor of V{gamma}9V{delta}2 T cells BTN3A on lung tissues and cell lines as well as monocytes C_LIO_LIDuring SARS-CoV-2 infection, V{gamma}9V{delta}2 are differentiated and efficiently degranulate and secrete cytokines upon activation with BTN3A mAb C_LI

immunology↗