Dechanet-Merville, J. | Search bioRxiv

bioRxiv2024

Ephrin-A2 and Phosphoantigen-Mediated Selective Killing of Medulloblastoma by γδT Cells Preserves Neuronal and Stem Cell Integrity

Medulloblastoma (MB) is a pediatric brain tumor that develops in the cerebellum, representing one of the most common malignant brain cancers in children. Standard treatment includes surgery, chemotherapy, and radiation, but despite a 5-year survival rate of approximately 70%, these therapies often lead to significant neurological damage in the developing brain. This underscores the urgent need for less toxic, more effective therapeutic alternatives. Recent advancements in cancer immunotherapy, including immune checkpoint inhibitors and CAR-T cell therapy, have revolutionized cancer treatment. One promising avenue is the use of Gamma Delta ({gamma}{delta})T cells, a unique T cell population with potential advantages such as non-alloreactivity, potent tumor cell lysis, and broad antigen recognition. However, their capacity to recognize and target MB cells remains underexplored. To investigate the therapeutic potential of {gamma}{delta}T cells against MB, we analyzed the proportion and status of MB-infiltrated {gamma}{delta}T cells within patient datasets. We next investigated the expression of {gamma}{delta}T cell ligands on MB cells and identified EphA2 receptor and the phosphoantigen/Butyrophilin complex as key ligands, activating V{gamma}9V{delta}1 and V{gamma}9V{delta}2 T cells, respectively, leading to significant MB cell lysis in both monolayer and spheroid models. Importantly, preliminary safety data showed that {gamma}{delta}T cells did not target differentiated neurons or neuroepithelial stem cells derived from induced pluripotent stem cells, underscoring the selectivity and safety of this approach. In conclusion, {gamma}{delta}T cells trigger an efficient and specific killing of MB, and would offer a promising novel therapeutic strategy. Key messagesMedulloblastoma patients often experience significant long-term side effects from current standard treatments. Immunotherapy has emerged as a promising alternative to conventional therapeutic approaches. In our study, we demonstrated that {gamma}{delta}T cells can efficiently and specifically target medulloblastoma cells without causing harm to healthy neuronal tissue. These findings suggest that {gamma}{delta} T cell therapy may provide therapeutic benefits while potentially reducing treatment-related toxicity in medulloblastoma patients.

cancer biology↗

bioRxiv2022

Long-lived central memory γδ T cells confer protection against murine cytomegalovirus reinfection

The involvement of {gamma}{delta} TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. {gamma}{delta} T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of {beta} T cell deficient mice in order to analyze the memory potential of {gamma}{delta} T cells. As for CMV-specific {beta} T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ {gamma}{delta} TEM that principally localized in infected organ vasculature. Typifying T cell memory, {gamma}{delta} T cell expansion/proliferation in organs and blood was higher and more efficient after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection involved the T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR {delta} chain repertoire as evidenced by next generation sequencing. The {gamma}{delta} T cell secondary response to MCMV was composed by a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, Long-term-primed {gamma}{delta} TCM cells, but not {gamma}{delta} TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. Overall, our study uncovered memory properties of long-lived TCM {gamma}{delta} T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches. AUTHOR SUMMARYCytomegalovirus (CMV) is a widespread, latent virus that can cause severe organ disease in immune-compromised patients. Anti-CMV memory immune responses are essential to control viral reactivation and/or reinfection events that commonly take place in solid organ transplantation. The role of {gamma}{delta} T-cell receptor bearing lymphocytes could be crucial in this context where immunosuppressive/ablative treatments cause suboptimal and/or delayed {beta} T cell responses. Here we asked whether {gamma}{delta} T cells could compensate for the absence of {beta} T cells in the long-term control of mouse CMV infection. Three months post-primary viral challenge in {beta}-T cell deficient mice, {gamma}{delta} T cells displayed similar features as cytolytic, CMV-specific {beta} CD8 T cells. We showed that previous priming with CMV endowed {gamma}{delta} T cells with an enhanced antiviral potential and that long-term maintenance of {gamma}{delta}-mediated antiviral protection was dependent on {gamma}{delta} central memory T cells (TCM). The {gamma}{delta} T cell response to a secondary CMV challenge was dependent on {gamma}{delta} TCR-signaling and generated a private TCR {delta} repertoire as observed in human. Our results sustain the adaptive-like properties of these unconventional T cells and reveal the interest of targeting {gamma}{delta} TCM subset in novel antiviral vaccination approaches.

immunology↗