Exploring the immunologic consequences of ATRX deficiency in glioma

Author

Benjamin WhitfieldFollow

Author ORCID Identifier

0000-0002-2624-8464

Date of Graduation

5-2025

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Jason Huse

Committee Member

Jian Hu

Committee Member

Seyed Moghaddam

Committee Member

Wendy Woodward

Committee Member

Ahsan Farooqi

Abstract

ATRX is a key chromatin regulator that is frequently mutated across multiple cancer types. One of the most common ATRX-mutated tumor types is the adult-type glioma, IDH-mutant, Astrocytoma. It is known that ATRX mutation leads to increases in DNA damage, replication stress, and global epigenetic regulation at a cell level; however, less is known about the impact of ATRX mutation on immune signaling. Furthermore, little is known about the interaction of ATRX loss with gain-of-function mutations in IDH. In this paper we set out to explore the impact of ATRX loss on immune signaling in gliomas, both in the context or and absence of IDH mutation. We generated ATRX knockout murine gliomas with both CRISPR knock-out and the Tva-RCAS system, as well as generating a single-cell RNA sequencing data set from the CD45-sorted immune component of human ATRX-deficient Astrocytoma and ATRX-intact Oligodendroglioma. In our murine models, we observed that ATRX-deficient tumors displayed immune dependent increases in survival and transcriptional upregulation of key immune gene sets. Alongside this, we observed an increased innate immune signaling in response to PolyIC agonism and STING agonism, which was observed at the protein level, RNA level, and functional level via cytokine expression. The observed increase in immune signaling was dampened by IDH-mutation, and inhibition of mutant IDH relieved this dampening. Further, in our immune cell enriched, single cell sequencing from human tumors, we observed that that astrocytoma-associated immune cells display an upregulation of immune gene sets relative to oligodendroglioma-associated immune cells. Taken together these observations suggest that ATRX deficiency can drive anti-tumor immune activation, and that these immune perturbations can be observed in both murine and human contexts.

Keywords

Glioma, Neuro-oncology, Immunology, ATRX biology, Tumor immunology