ATRX mutations, innate immune activation and therapeutic vulnerability in malignant gliomas

ABSTRACT
Gliomas, including oligodendroglioma and astrocytoma subtypes, are a diverse group of malignant primary
brain tumors that respond to radiation, surgery and chemotherapy; however, relapse remains a major barrier
affecting overall patient survival. Immunotherapy targeting the adaptive immune system such as checkpoint
inhibitors has shown limited efficacy in gliomas. Thus, understanding the immunobiology of gliomas and
mechanisms of resistance to immune therapies is crucial to therapeutically leverage the immune system for
treating patients. Our long-term goal is to dissect the innate immune system in gliomas and identify vulnerabilities
that can be exploited for designing therapies.
Recent studies have implicated a link between mutations in ATRX, a SWI-SNF chromatin remodeler and
immune cell infiltration in the tumor microenvironment of ATRX-mutant astrocytomas. Our preliminary data
suggest that ATRX inactivation in gliomas leads to enriched inflammatory signatures and potentiation of type I
interferon/pro-inflammatory signaling, and selective sensitization of tumors to double-stranded (dsRNA)-based
immune agonists. Based on these preliminary findings, we hypothesize that ATRX inactivation induces innate
inflammation and sensitizes tumors to immune surveillance and dsRNA agonist therapy; concurrent IDH
mutations suppress innate inflammation to enable tumor immune evasion. We will test our hypothesis in the
following specific aims. Aim 1: Define the role of ATRX inactivation in modulating glioma cell-intrinsic innate
signaling; Aim 2: Elucidate the role of ATRX deficiency and concurrent IDH1R132H mutation in modulating anti-
tumor immunity and the response to dsRNA agonist therapy in pre-clinical murine glioma models; Aim 3:
Determine the extent to which dsRNA-based therapies induce inflammatory activation of lower-grade gliomas.
Our proposal will: 1) delineate the novel role of ATRX loss in regulating innate immune signaling responses
and their downstream effects in glioma, 2) examine the immunological interplay between ATRX mutations and
its partner mutation, IDH1R132H and 3) lay preclinical groundwork for exploiting a potential therapeutic vulnerability
in gliomas carrying ATRX mutations.

Grant Number: 4R01CA255788-04
NIH Institute/Center: NIH
Principal Investigator: David Ashley