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

The efficacy of T cell-dependent immunotherapies against glioma is limited by few intra-tumoral lymphocytes and tumor-induced T cell sequestration. We considered whether peripheral autologous lymphocyte transfer (ALT) could boost Central Nervous System (CNS) T cell counts in established glioma. We found that ALT lymphocytes specifically entered tumor tissue while endogenous T cell counts fell. T cells expanded with IL-7 demonstrated an enhanced ability to accumulate in established murine glioma compared to IL-2. Increased entry was not phenotype dependent. Instead, IL-7 upregulates the migratory integrin VLA-4 on mouse and human T cells. VLA-4 expression was also high on endogenous T cells in established tumors. Intracranial (IC) VLA-4 blockade retained T cells in the brain but did not yield any survival benefit. IC VLA-4 blockade also reduced the cytotoxicity of immunotherapies in vitro. However, combination IL-7 ALT (VLA-4Hi) & α4-1BB antibody therapy extended median survival for animals with orthotopic glioma compared to monotherapy. Similarly, IL-7 expanded hPBMCs & brain bi-specific T cell engagers targeting EGFRvIII (BRiTE) extended survival. We conclude that IL-7 upregulates VLA-4 on T cells, facilitating their accumulation in IC glioma. Seeding gliomas with infiltrative T cells is a potential therapeutic strategy to enhance the efficacy of T-cell dependent therapies.