CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: The effectiveness of immunotherapies against glioblastoma (GB) remains limited. A major obstacle in advancing new strategies is the reliance on non-autologous systems, which do not accurately mimic the true extent of inter-patient heterogeneity in both immune responses and tumor susceptibility. This often leads to misleading conclusions about therapeutic efficacy and targetability. METHODS: In this study, we addressed this critical gap by employing a fully autologous model. We phenotypically characterized primary and T cells from the peripheral blood and tumors of 40 brain tumor patients, including 36 with confirmed GB, and expanded and functionally assessed the autologous anti-GB reactivity in a subset of patients. RESULTS: Notably, only V 2 + and V 2 - T cells, but not T cells, recognized autologous tumors. While V 2 - T cells showed activity in a subset of patients, V 2 + TILs from all patients responded to autologous GB cells in the presence of pamidronate. In patients, a higher percentage of V 2 + TILs was associated with longer overall survival. However, the potency of V 2 + TILs varied markedly between individuals, highlighting substantial inter-patient heterogeneity in T cell-mediated tumor recognition. This variability was driven by differences in both immune cell-intrinsic features and tumor-intrinsic factors, including expression of BTN2A1 and especially BTN3A, the ligands of the V 2 + TCR. Functional assays revealed that anti-GB reactivity was further modulated by stimulatory and inhibitory co-receptors such as NKG2D, CD94, and TIGIT. Transcriptomic analysis linked V 2 + T cell reactivity to extracellular matrix (ECM) pathways and disrupting ECM components such as LAMA5 and TGFB1 enhanced T cell responses. Knockout of ITGA3, a LAMA5 receptor, increased BTN2A1 and BTN3A expression on GB cells, improving immune recognition. CONCLUSIONS: This study demonstrates that inter-patient heterogeneity in V 2 + TIL responses to GB is driven by the extracellular matrix-BTN3A axis. Autologous systems effectively capture this heterogeneity, offering a reliable platform to identify determinants of both immune function and tumor vulnerability, insights that are essential for the rational design of TIL-based immunotherapies.