Biology subjects

Scotet, E.

Publications and source records attributed to Scotet, E..

3 recordsLinked to original sources

bioRxiv2026

Functional diversity of Vγ9Vδ2 T cells overcomes glioblastoma state plasticity and antigen heterogeneity

Glioblastoma (GBM) is characterized by a high degree of cellular plasticity and intra-tumoral heterogeneity, which frequently leads to the failure of standard therapies, including immunotherapies. While chimeric antigen receptor (CAR) T cells offer a potent means of MHC-independent tumor recognition, their efficacy is hampered by the coexistence of distinct molecular states, gathered as proneural (PN) and mesenchymal (MES) phenotypes. Here, we demonstrate that gangliosides GD2 and O-acetylated GD2 (OAcGD2) are preferentially expressed by PN cells whereas MES cells display reduced expression due to upregulated ganglioside catabolism. Conversely, MES cells are known to exhibit high expression of stress-induced ligands recognized by V{gamma}9V{delta}2 T cells. We show that while engineering V{delta}2T cells with GD2- or OAcGD2-specific CAR enables the elimination of PN cells, it also facilitates the immune escape of MES cells in heterogeneous 3D-tumoroid models. Mechanistically, we reveal a hierarchy of receptor engagement, where CAR signaling predominates leading to the structural and functional exclusion of endogenous TCR from the immunological synapse. To address this receptor competition, we propose a strategy that leverages the functional effector diversity by combining untransduced and CAR-engineered V{delta}2T cells. This dual approach provides a dynamic safety net by ensuring the simultaneous elimination of PN and MES cells and preventing the selective outgrowth of resistant cells. Our findings establish a conceptual framework for designing off-the-shelf immunotherapies tailored to the metabolic and phenotypic plasticity of resistant solid tumors.

cancer biology↗

bioRxiv2026

Optimized Multiple Amplification Protocol for the Production of Allogeneic Human Vγ9Vδ2 T Lymphocytes for Adoptive Cell Transfer Immunotherapy

Cancer remains a major therapeutic challenge despite substantial advances in diagnosis and treatment, including immune checkpoint blockade. Among emerging immunotherapeutic approaches, adoptive cell transfer (ACT) has attracted growing interest. Human peripheral V{gamma}9V{delta}2 T cells are promising candidates for ACT because they combine rapid and potent antitumor functions with major histocompatibility complex (MHC)-independent tumor recognition, enabling allogeneic use with limited risk of graft-versus-host disease. This raises the possibility of generating standardized V{gamma}9V{delta}2 T-cell banks from healthy donors for off-the-shelf immunotherapy. Here, we provide preclinical evidence supporting the suitability of allogeneic human V{gamma}9V{delta}2 T cells for ACT. We characterized peripheral blood V{gamma}9V{delta}2 T cells from healthy donors after successive antigen-specific and non-specific amplification steps, assessing their phenotype, effector functions, and metabolic state. Amplified cells maintained a strong pro-inflammatory Th1-like profile, preserved cytotoxic activity, and did not produce immunoregulatory cytokines. They also displayed high purity, a predominant effector memory phenotype, reduced expression of several inhibitory immune checkpoints, and sustained antitumor reactivity. Altogether, these findings support the development of allogeneic V{gamma}9V{delta}2 T-cell products as a scalable platform for next-generation cancer immunotherapies.

immunology↗

bioRxiv2023

Targeting human γδ T cells as a potent and safe alternative to pan-T cells bispecific cell 2 engagers

Over the past decade, an increasing number of immunotherapies aiming to improve the ability of the immune system to effectively eradicate tumor cells have been developed. Among them, targeting effector T cell subsets of the immune system with bispecific antibodies, called T Cell Engagers (TCEs), represents an attractive strategy. TCEs are designed to specifically direct cytotoxic T cells towards tumor cells, thereby inducing a strong activation leading to the lysis of tumor cells. New strategies for targeting specific T-cell subsets are currently being explored. In this study, we investigated the activity of different TCEs on both conventional alpha beta ({beta}) T cells and unconventional gamma delta ({gamma}{delta}) T cells. We generated TCE molecules based on camelid single-domain antibodies (VHHs) that target the tumor-associated antigen CEACAM5 (CEA), together with particular T-cell receptor chains (TCRs) or a CD3 domain. The in vitro biological activity of the TCEs against the colon carcinoma cell line LS174T was measured using fresh and cultured human V{gamma}9V{delta}2 and {beta} T cells. We showed that V{gamma}9V{delta}2 T cells display stronger antitumor activity in vitro than {beta} T cells when activated with a CD3xCEA TCE. Furthermore, restricting T cell activation to V{gamma}9V{delta}2 T cells limits the production of pro-tumor factors and pro-inflammatory cytokines, which are often associated with toxicity in patients. Taken together, these results suggest that V{gamma}9V{delta}2{gamma}{delta} T cell-specific TCEs may represent safe, novel, specific, and effective molecules for improving antitumor immunotherapies.

immunology↗