Friday, November 22, 2024
11/22/2024
ABSTRACT Astrocytomas (WHO grade II and III) primarily occur in early-middle adult life. Most lower grade astrocytoma progress to higher grade including GBM (i.e., secondary GBM) despite the best standard-of-care therapy. Developing more effective therapeutic strategies requires a more complete understanding of the mechanisms employed by astrocytoma cells to escape anti-tumor immunity. The majority (~80%) of grade II & grade III astrocytoma carry mutations in isocitrate dehydrogenase (e.g., IDH1R132H), which typically occurs with p53 mutation and ATRX inactivation (i.e., IDH1R132H/p53mut/ATRXloss, triple-mut for simplicity), indicating that this triple mutation background has an important role in tumor growth potentially including immune evasion mechanisms. However, our current understanding of how triple-mut astrocytoma cells modulate the tumor microenvironment (TME) to suppress anti-tumor immunity is limited and inadequate. The goal of this project is to elucidate the cellular and molecular mechanisms by which triple-mut astrocytoma cells modulate TME immune cells and use these discoveries to develop novel strategies to sensitize triple-mut astrocytoma cells to emerging immunotherapeutics. Our recent published findings and preliminary data show that triple-mut induces multiple pathways critical to anti-tumor immunity including checkpoint ligands, IFN-γ signaling insensitivity, down- regulation of MHC-I and -II antigen presentation pathways (MHC APP), and dysregulated cytokine/chemokine profiles that modulate the astrocytoma immune microenvironment. Furthermore, we found that the components of the immune-modulating astrocytoma transcriptome are augmented by standard-of-care radiation (IR) and temozolomide (TMZ). Our findings implicate BET and EHMT as epigenetic determinants of astrocytoma immune- modulating transcriptome. Building on these interesting findings, we will pursue the following specific aims: (i) Determine the role of BETs in the immune-suppressive transcriptome in triple-mut astrocytoma cells at baseline and in response to standard-of-care radiation; (ii) Identify EHMT-dependent methylation events that drive IFN signaling insensitivity and MHC APP down-regulation in triple-mut astrocytoma cells; (iii) Determine if BET and EHMT inhibition in combination reprogram astrocytoma microenvironment and sensitize astrocytoma to anti- CTLA-4 therapy. These experiments will fill critical knowledge gaps in our understanding of BET-dependent and EHMT-dependent immunomodulatory pathways underlying astrocytoma cell: immune cell immunosuppressive interactions and their augmentation by IR and establish the potential for combinational strategies to sensitize triple-mut astrocytoma to emerging immunotherapeutics.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
