Abstract 6191: Temozolomide-associated DNA damage processes related to glioblastoma-immune interactions

Abstract

Abstract How do cancer cells convert an external perturbation into an interaction with the immune system? The processes associated with antigen presentation remain largely unknown, especially in cancer cells responding to treatment. These intracellular changes may be critical in cancers where immunotherapies need significant optimization, such as glioblastoma. Glioblastoma is also a particularly relevant cancer to characterize the cellular response to perturbations, since all patients currently receive temozolomide, an alkylating agent, regardless of their prognosis. We used mass spectrometry methods to quantify temozolomide-associated changes to the repertoire of peptides presented on MHC class I molecules in vitro over time, as well as the associated changes that occur in DNA damage signaling and protein synthesis. We treated U87-MG cells with temozolomide and directly profiled the peptide-MHC repertoire, ATM/ATR kinase substrate phosphorylation, and newly-synthesized proteins via isotopically labeled and non-canonical amino acid-tagged proteins after 24, 48, and 72 hours. These proteomics approaches identified several MHC-peptides, including phosphorylated peptides, whose presentation changes over time after treatment with temozolomide. We also found that the temporal dynamics of the DNA damage response mirrored that of immunopeptidome remodeling. Additionally, temozolomide alters translation at these time points, with newly-synthesized proteins reflecting internal cell stress processes. These findings suggest potential treatment-associated antigens against which to design vaccines as well as particular signaling nodes that could be modulated with combination therapies to improve presentation of these peptides. Citation Format: Elizabeth Y. Choe, Forest M. White. Temozolomide-associated DNA damage processes related to glioblastoma-immune interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6191.