Noldner, P. | Search bioRxiv

bioRxiv2025

A Spatial Multi-Omic Framework Identifies Gliomas Permissive to TIL Expansion

Tumor-infiltrating lymphocyte (TIL) therapy is effective in several tumor types; however, its feasibility in immune subversive tumors like glioblastoma is unclear. We expanded TILs from glioblastoma specimens and observed marked variability in yield, composition, function, and TCR clonality. By interrogating TILs expanded ex vivo alongside their sourced glioma tissue, we sought to identify determinants of successful (TIL+) vs unsuccessful TIL expansion (TIL-). Expanded TILs were predominantly effector memory CD4 cells and exhibited oligoclonal TCR enrichment. Despite similar T cell abundance in TIL vs TIL- tumors, TIL tumors exhibited distinct spatial organization and cellular interactions, including increased endothelial-immune interactions/ proximity and enrichment of vascular-associated niches. CD4 T cells localized near CD68 macrophages in TIL tumors, while they were positioned near CD163 CD206 macrophages in TIL- tumors. Thus, TIL expansion and functionality are linked to spatial organization and myeloid context; these features may enable biomarker-driven stratification for future TIL therapy in gliomas.

cancer biology↗

bioRxiv2024

IL-7 mediated upregulation of VLA-4 increases accumulation of adoptively transferred T lymphocytes in murine glioma.

The efficacy of T cell-activating therapies against glioma is limited by an immunosuppressive tumor microenvironment and tumor-induced T cell sequestration. We investigated whether peripherally infused non-antigen specific autologous lymphocytes (ALT) could accumulate in intracranial tumors. We observed that non-specific autologous CD8+ ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared to IL-2. Pre-treatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and non-tumor-specific T cell-dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, we detected increased VLA-4 on mouse and human CD8+ T cells following IL-7 expansion, with increased transcription of genes associated with migratory integrin expression (CD9). We also observed that IL-7 increases S1PR1 transcription in human CD8+ T cells, which we have shown to be protective against tumor-induced T cell sequestration. These observations demonstrate that expansion with IL-7 enhances the capacity of ALT to accumulate within intracranial tumors, and that pre-treatment with IL-7 ALT can boost the efficacy of subsequent T cell-activating therapies against glioma. Our findings will inform the development of future clinical trials where ALT pre-treatment can be combined with T cell-activating therapies. Brief SummaryT cell immunotherapies are limited by few T cells in glioma. Adoptively transferred lymphocytes expanded with IL-7 exhibit increased VLA-4 expression and accumulate in tumors.

cancer biology↗