Gliomas are devastating central nervous tumors that are associated with an immunosuppressive
network impacting the tumor microenvironment, bone marrow and the peripheral blood
compartments. The development of novel biomarkers of cancer immunity have not kept pace with
breakthroughs in our understanding of cancer-associated inflammation and its relationship with
abnormal hematopoiesis and the production of myeloid related suppressor cells (MDSC). This gap in
our understanding is a recognized high priority in the new era of cancer immunotherapy. The Cancer
Moonshot blue ribbon panel recommended as a key actionable goal ?to develop approaches to
overcome an obstructive, immune-suppressive tumor environment in both children and adults?. Our
project addresses this important goal by developing and testing a highly innovative approach for
measuring immunosuppression in glioma patients. In Aim 1 we will augment our validated epigenetic
bioinformatic approach for leukocyte profiles to include both granulocytic and monocytic MDSCs. We
use specific DNA methylation changes as quantitative markers of immune cell types. In Aim 2 we will
then assess the predictive value of methylation generated immune profiles (CD4, CD8, T-cells, B-
cells, NK, monocytes, neutrophils, gMDSC, mMDSC) in glioma patient progression and survival.
Patients will be carefully selected from the UCSF Adult Glioma Study to represent key molecular
genetic subtypes of glioma using three diagnostic gene mutations (IDH, TERT, 1p19q deletion). We
then will validate the blood immune profiles in an independent population of glioma patients from the
Mayo Clinic. We will also augment Aim 2 by oversampling an uncommon and poorly understood
subset of glioma patients whose tumors do not contain any of the three cardinal mutations (i.e. triple
negative glioma). To explore the relationship of blood and tumor immune profiles we will apply
genome wide methylation assay to tumors in Aim 3 from patients with matched blood samples from
UCSF. We will then replicate tumor blood correlations within the Mayo Clinic patient population. This
comprehensive program will develop new tools to characterize the destructive immune suppression in
glioma patients. Our epigenetic immune approach is highly flexible and cost effective and will provide
a major advance for evaluating immune factors in glioma treatment and outcomes.
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