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

in The Journal of clinical investigation by 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

TLDR

  • The study shows that pre-treatment with IL-7 autologous lymphocytes enhances the efficacy of T cell-activating therapies against glioma by increasing T cell accumulation in the tumor microenvironment.

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 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.

Overview

  • The study investigates whether peripherally infused non-antigen specific autologous lymphocytes (ALT) can accumulate in intracranial tumors.
  • The researchers observed that non-specific autologous CD8+ ALT cells can accumulate in the tumor microenvironment, despite endogenous T cell sequestration in bone marrow.
  • IL-7 was found to be more effective in expanding lymphocytes compared to IL-2, leading to increased intratumoral accumulation and enhanced efficacy of T cell-dependent immunotherapies against glioma.

Comparative Analysis & Findings

  • The study compared the accumulation of ALT cells in intracranial tumors when expanding lymphocytes with IL-7 versus IL-2, showing that IL-7 increased rates of accumulation.
  • The researchers also compared the efficacy of T cell-activating therapies against glioma with and without pre-treatment with IL-7 ALT, finding that pre-treatment with IL-7 ALT enhanced the efficacy of multiple immunotherapies.
  • The study detected increased expression of VLA-4 and CD9 on CD8+ T cells following IL-7 expansion, as well as increased transcription of S1PR1 in human CD8+ T cells, which was shown to be protective against tumor-induced T cell sequestration.

Implications and Future Directions

  • The study's findings suggest that pre-treatment with IL-7 ALT can be used to enhance the efficacy of T cell-activating therapies against glioma, and that future clinical trials should investigate this approach.
  • The study highlights the need to further investigate the mechanisms by which IL-7 promotes T cell accumulation in intracranial tumors, and to identify potential biomarkers for predicting treatment response.
  • The researchers propose that future studies explore the combination of IL-7 ALT pre-treatment with other immunotherapies, as well as the development of new methods for delivering and targeting ALT cells to the tumor microenvironment.
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