IMMU-04. Unleashing Vδ2+ γδTILs in Glioblastoma: Overcoming the Maze of Tumor Evasion

Abstract Glioblastoma (GB) remains the most aggressive primary brain tumor with a poor patient prognosis. Immunotherapeutic strategies are emerging as an interesting option, however the effectivity of these therapies remains low, possibly due to tumor escape mechanisms. γδT cells have been identified as interesting effector cells for immunotherapeutic strategies as they possess anti-tumor characteristics against many cancers, including GB. However, analyses characterizing activity of γδT cells against GB in a completely autologous setting are scarce. In order to investigate the influence of T cells on GB tumors in an autologous setting, we phenotypically characterized αβ and γδT cells infiltrating in the tumor and originating from peripheral blood of 36 GB patients and expanded different T cell subsets from a selection of patients (n=9) in vitro. We showed that the most prevalent T cells, αβT cells, from both tumor and peripheral blood did not show any reactivity against autologous GB tumors, while Vδ2+ and Vδ2- γδT cells were able to recognize their autologous tumor. We witnessed that γδTILs were more active than matched PBMC-derived γδT cells and highest recognition was seen for Vδ2+ TILs, however, substantial heterogeneity in potency was observed. Interestingly, Vδ2+ TILs often used multiple receptors for recognition of GB tumor cells, which varied per patient. Also, primary GB tumors showed great heterogeneity. Combined flow cytometry and transcriptomic analysis of 5 patient-derived tumors highlighted that not only different levels in BTN2A1 and BTN3A, the natural targets for Vδ2+ TCR activation, impacted recognition, but also expression of extracellular matrix related genes. One of these genes, ITGA3, was found to modulate BTN2A1 and BTN3A expression levels, suggesting a role as a novel tumor escape mechanism for preventing Vδ2+ T cell recognition.