IL-7–mediated expansion of autologous lymphocytes increases CD8⁺ VLA-4 expression and accumulation in glioblastoma models

• Text
• PDF

Abstract

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 nonantigen specific autologous lymphocytes could accumulate in intracranial tumors. We observed that nonspecific 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 with IL-2. Pretreatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and nontumor-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 pretreatment 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 pretreatment can be combined with T cell–activating therapies.

Authors

Kirit Singh, Kelly M. Hotchkiss, Sarah L. Cook, Pamy Noldner, Ying Zhou, Eliese M. Moelker, Chelsea O. Railton, Emily E. Blandford, Bhairavy J. Puviindran, Shannon E. Wallace, Pamela K. Norberg, Gary E. Archer, Beth H. Shaz, Katayoun Ayasoufi, John H. Sampson, Mustafa Khasraw, Peter E. Fecci