Abstract A11: Ipilimumab protects T cells from the antiproliferative effects of dexamethasone

Abstract

Background: Checkpoint inhibitor blockade, designed to activate antitumor immune cells, is gaining enthusiasm as a potential treatment modality for patients with brain tumors. However, adjuvant therapies aimed at killing tumor (i.e., chemotherapy) or reducing tumor-related edema (i.e., corticosteroids) are often cytotoxic to lymphocytes. Yet, whether tumor-specific T cells are harmed during corticosteroid treatment is not known. Methods: The effects of dexamethasone on healthy donor T cells was tested in vitro for T cell proliferation, cell cycle analysis, glucose uptake, transcriptional changes, and protein expression. The effects of dexamethasone and CTLA-4 antibody blockade were tested in vivo using the GL261 murine glioblastoma model. Results: Here we show that dexamethasone blocks proliferation of naive human T cells but not memory T cells. We find that dexamethasone inhibits early stages of T cell proliferation by impairing CD28-mediated cell cycle entry. Dexamethasone induced a fourfold increase in surface CTLA-4 during T cell stimulation, and neutralizing CTLA-4 with ipilimumab overcame the dexamethasone-induced blockade of cell cycle entry in vitro. Further, CTLA-4 blockade in combination with dexamethasone provided a survival benefit in vivo to mice bearing orthotopic GL261 brain tumors. Intriguingly, early dexamethasone treatment afforded the greatest survival advantage Conclusions: These findings shed light on the T cell-specific effects of dexamethasone and suggest that antigen-experienced T cells are resistant to anti-proliferative effects of corticosteroids. These findings have important implications for patients receiving immune therapy who may benefit from the anti-inflammatory properties of dexamethasone. Citation Format: Amber J. Giles, Marsha-Kay N.M. Hutchinson, Heather Sonnemann, Caitlin M. Reid, Jinkyu Jung, Wei Zhang, Hua Song, Rolanda Bailey, Dionne Davis, Deric M. Park, Mario Roederer, Mark R. Gilbert. Ipilimumab protects T cells from the antiproliferative effects of dexamethasone [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A11.