Preclinical Modeling of Surgery and Steroid Therapy for Glioblastoma Reveals Changes in Immunophenotype that are Associated with Tumor Growth and Outcome.

Journal Article (Journal Article)

PURPOSE: Glioblastoma (GBM) immunotherapy clinical trials are generally initiated after standard-of-care treatment-including surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment-has either begun or failed. However, the impact of these interventions on the antitumoral immune response is not well studied. While discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated into clinical trial design, the impact of surgical resection and steroids on the antitumor immune response has yet to be determined. EXPERIMENTAL DESIGN: We developed a murine model integrating tumor resection and steroid treatment and used flow cytometry to analyze systemic and local immune changes. These mouse model findings were validated in a cohort of 95 patients with primary GBM. RESULTS: Using our murine resection model, we observed a systemic reduction in lymphocytes corresponding to increased tumor volume and decreased circulating lymphocytes that was masked by dexamethasone treatment. The reduction in circulating T cells was due to reduced CCR7 expression, resulting in T-cell sequestration in lymphoid organs and the bone marrow. We confirmed these findings in a cohort of patients with primary GBM and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Finally, we demonstrated that peripheral lymphocyte content varies with progression-free survival and overall survival, independent of tumor volume, steroid use, or molecular profiles. CONCLUSIONS: These data reveal that prior to intervention, increased tumor volume corresponds with reduced systemic immune function and that peripheral lymphocyte counts are prognostic when steroid treatment is taken into account.

Full Text

Duke Authors

Cited Authors

  • Otvos, B; Alban, TJ; Grabowski, MM; Bayik, D; Mulkearns-Hubert, EE; Radivoyevitch, T; Rabljenovic, A; Johnson, S; Androjna, C; Mohammadi, AM; Barnett, GH; Ahluwalia, MS; Vogelbaum, MA; Fecci, PE; Lathia, JD

Published Date

  • April 1, 2021

Published In

Volume / Issue

  • 27 / 7

Start / End Page

  • 2038 - 2049

PubMed ID

  • 33542075

Pubmed Central ID

  • PMC8026586

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-20-3262

Language

  • eng

Conference Location

  • United States