Biology subjects

Alcain, J.

Publications and source records attributed to Alcain, J..

6 recordsLinked to original sources

bioRxiv2025

Differential CD8+ T/NK cell-mediated reduction of HIV-1 replication after combination of ART with TIGIT or KLRG1 blockade in humanized mice

Expression of TIGIT and KLRG1 has been associated to an exhausted, dysfunctional state in natural killer (NK) and CD8+ T cells from people with HIV-1 (PWH), limiting the efficacy of immunotherapies aiming at achieving a functional cure of the infection. Antiretroviral therapy (ART) does not completely reverse this immune exhaustion, and its combination with blockade of immune checkpoint receptors such as TIGIT and KLRG1 could be a promising strategy to promote control of viral replication in PWH. However, the impact of targeting these two immune checkpoint receptors has not been evaluated in vivo. In this study, we used a humanized Bone Marrow, Liver and Thymus (hBLT) mouse model of HIV-1 infection to study the impact of ART in combination with aTIGIT or aKLRG1 or a bispecific aTIGIT/aKLRG1 mAbs. Our results indicated that combination of ART with either aTIGIT or aKLRG1 mAbs led to faster reduction of HIV-1 pVL. Furthermore, viral rebound after ART interruption (ATI) was delayed in mice treated with aTIGIT and aKLRG1 mAbs. Histological detection of HIV-1 p24 in the spleen was restricted to the white pulp in the aKLRG1 mAb-treated group, which correlated with higher infiltration of IFN{gamma}+ CD8+ T cells in these histological regions and with increased cytotoxic CD107a+ Granzyme B+ CD8+ T cells in the spleen. In contrast, control of HIV-1 replication induced by the aTIGIT mAb was associated with an increased splenic CD107a+ IFN{gamma}+ NKG2C+ CD57-adaptive NK cells. In contrast, combination of ART with a bispecific aTIGIT/aKLRG1 mAb was unable to efficiently suppress viral replication or delay viral rebound after ATI, potentially by inducing apoptosis of adaptive NKG2C+ NK. Together, these results suggest that combination of ART with individual TIGIT or KLRG1 blockade may be a promising immunotherapy strategy against HIV-1 by eliciting differential immune control mechanisms.

immunology↗

bioRxiv2025

A tumor suppressor role of the miR-15b/16-2 cluster in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising from the neoplastic transformation of immature T cells during their development in the thymus. Deciphering the developmental programs whose dysregulation leads to T-ALL pathogenesis is critical for the development of novel targeted therapies, which remain an urgent unmet need for the treatment of this disease. MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of numerous physiological processes and cancer. However, the specific role of miRNAs in human T-cell development and T-ALL pathogenesis remains largely unexplored. In this study, we comprehensively evaluated miRNA expression profiles across human T-cell development by microarray analysis and identified a dynamic expression pattern of miR-16-2, which is upregulated across early pre-T cell proliferative stages up to the resting stage of immature thymocytes immediately preceding TCR{beta} expression, and decreased thereafter. We confirmed the coordinated regulation of miR-15b expression, consistent with the reported clustered genomic location of both miRNAs. Notably, functional studies identified the miR-15b/16-2 cluster as a negative regulator of early thymocyte proliferation, and showed that overexpression of miR-15b/16-2 in T-ALL cells impaired leukemic growth in vitro and tumor progression in patient-derived xenotransplantation assays. Mechanistically, miR-15b/16-2 expression represses the genes encoding BCL-2 and CYCLIN D3, leading to T-ALL apoptosis and cell cycle dysregulation, with an accumulation of G0-phase cells and a defective transition to the G2/M phase. Overall, these findings support a novel function for miR-15b/16-2 as tumor suppressors in T-ALL, highlighting their role as promising targets for T-ALL therapy. KEY POINTSO_LImiR-15b/16-2 overexpression impairs the proliferation of human thymic progenitors leading to defective T-cell production. C_LIO_LImiR-15b/16-2 represses BCL-2 and CYCLIN D3 expression and impairs tumor progression in human T-ALL, revealing its role as tumor suppressor. C_LI

immunology↗

bioRxiv2024

CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by high rates of induction failure and relapse, and effective targeted immunotherapies are lacking. Despite promising clinical progress with genome-edited CD7-directed CAR-T cells, which present significant logistical and regulatory issues, CAR-T cell therapy in T-ALL remains challenging due to the shared antigen expression between malignant and healthy T cells. This can result in CAR-T cell fratricide, T cell aplasia, and the potential for blast contamination during CAR-T cell manufacturing. Recently, CAR-T cells have been described that target non-pan-T antigens, absent on healthy T cells but expressed on specific T-ALL subsets. These antigens include CD1a (NCT05679895), which is expressed in cortical T-ALL, and CCR9. We show that CCR9 is expressed on >70% of T-ALL patients (132/180) and is maintained at relapse, with a safe expression profile in healthy hematopoietic and non-hematopoietic tissues. Further analyses showed that dual targeting of CCR9 and CD1a could benefit [~]86% of patients with T-ALL, with a greater blast coverage than single CAR-T cell treatments. We therefore developed, characterized, and preclinically validated a novel humanized CCR9-specific CAR with robust and specific antileukemic activity as a monotherapy in vitro and in vivo against cell lines, primary T-ALL samples, and patient-derived xenografts. Importantly, CCR9/CD1a dual-targeting CAR-T cells showed higher efficacy than single-targeting CAR-T cells, particularly in T-ALL cases with phenotypically heterogeneous leukemic populations. Dual CCR9/CD1a CAR-T therapy may prevent T cell aplasia and obviate the need for allogeneic transplantation and regulatory-challenging genome engineering approaches in T-ALL.

immunology↗

bioRxiv2024

Pre-TCR-Targeted Immunotherapy for T-cell Acute Lymphoblastic Leukemia

Targeted immunotherapy for T-cell acute lymphoblastic leukemia (T-ALL), an aggressive tumor of developing T-cell progenitors, is an urgent unmet need, especially for relapsed/refractory (r/r) disease. Selective T-ALL targeting is challenging due to the shared antigen expression between leukemic and normal T cells. Here we identify the pre-TCR, a surface receptor essential for T-cell development, as a biomarker of leukemia-initiating cells (LICs) in human T-ALL. Loss-of-function genetic approaches demonstrate that pre-TCR signaling is necessary for LIC activity and tumor progression in pre-TCR+ T-ALL patients xenografts. Furthermore, we demonstrate the specific therapeutic targeting of pre-TCR with a monoclonal antibody against the invariant pT subunit of the human pre-TCR, and validate an anti-pT antibody-drug conjugate treatment as a potent immunotherapy for inhibiting LIC activity and tumor progression of T-ALL in vivo. These findings reveal the suitability of pre-TCR targeting as a promising therapy for the treatment of (r/r) patients with T-ALL expressing the pre-TCR.

immunology↗

bioRxiv2024

Combined Dendritic Cell And Anti-TIGIT Immunotherapy Potentiate Trail+ Memory NK Cells Against HIV-1 Infected Cells

Natural Killer (NK) cells are promising tools for the development of immunotherapies targeting persistently infected CD4+ T cells to potentially achieve remission in people with HIV-1 (PWH). However, the chronicity of HIV-1 infection limits the functional properties of NK cells, and additional approaches are needed to potentiate their cytotoxic activity against HIV-1-infected cells. In the present study, we analyzed the reinvigoration of functional NK cells from PWH after priming with autologous dendritic cells (DC) stimulated with nanoparticles containing Poly I:C (Nano-PIC). We show that improved natural cytotoxic function in NK cell from PWH associates with increased proportions of NKG2C+CD57- precursors of memory NK, which eliminate HIV-1 infected CD4+ T cells mainly through the TRAIL receptor. In addition, expression of TIGIT but not TIM3 limited increase in NKG2C+ memory NK cell precursors and associated with persistent dysfunctionality of NK cells after stimulation with Nano PIC-DC. Blockade of TIGIT restored functional capacities of NK cell from PWH eliminating HIV-1 infected cells in vitro. Moreover, combining of NK cell and Nano-PIC-DC with anti-TIGIT mAbs immunotherapy limited the expansion of HIV-1 infected cells in humanized immunodeficient NSG mice transplanted with CD4+ T cells from PWH in vivo. Such viral control was associated with preserved NKG2C memory NK cell precursors, increased expression of granzyme B and TRAIL on NK in tissue from transplanted NSG mice. Together, combination of Nano-PIC DC and anti-TIGIT antibodies may be a promising strategy to increase the efficacy of immunotherapies aimed at HIV-1 cure. One sentence summaryStimulation of memory NK with a combination of DC and anti-TIGIT antibodies increase their ability to eliminate HIV-1 infected CD4+ T cells in vitro and in vivo.

immunology↗

bioRxiv2021

A novel bacterial protease inhibitor adjuvant in RBD-based COVID-19 vaccine formulations increases neutralizing antibodies, specific germinal center B cells and confers protection against SARS-CoV-2 infection.

In this work we evaluated recombinant receptor binding domain (RBD) based vaccine formulation prototypes with potential for further clinical development. We assessed different formulations containing RBD plus Alum, AddaS03, AddaVax or the combination of Alum and U-Omp19: a novel Brucella spp. protease inhibitor vaccine adjuvant. Results show that the vaccine formulation composed of U-Omp19 and Alum as adjuvants have a better performance: it significantly increased mucosal and systemic neutralizing antibodies in comparison to antigen plus Alum, AddaVax or AddaS03. Antibodies induced with the formulation containing U-Omp19 not only increased their neutralization capacity against the wild-type virus but also cross neutralized alpha, lambda and gamma variants with similar potency. Also, addition of U-Omp19 to vaccine formulation increased the frequency of RBD-specific geminal center B cells and plasmablasts. Additionally, U-Omp19+Alum formulation induced RBD-specific Th1 and CD8+ T cell responses in spleens and lungs. Finally, this vaccine formulation conferred protection against an intranasal SARS-CoV-2 challenge of K18-hACE2 mice.

immunology↗