# Modulation of Microglia and T Cell Interactions in Malignant Glioma

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $287,999

## Abstract

ABSTRACT
Immunotherapy has revolutionized cancer treatment by reversing the immune suppression of cytotoxic anti-
tumor CD8+ effector T cells. However, glioblastoma patients have profound lymphopenia and immune
checkpoint inhibition treatment does not restore T cell immune function. Extensive characterization by our group
has demonstrated that glioblastoma is fundamentally different relative to other malignancies in its preferential
enrichment of innate immune cells such as macrophages and microglia that are recruited to the tumor
microenvironment. These innate immune cells are tumor supportive. In a genetically-engineered mouse model
(GEMM) of glioblastoma we recapitulated lympophenia using a CD8 knockout (KO) background, and found
marked enrichment of PD-1 expressing macrophages in the murine glioma microenvironment – similar to
observations made in human glioblastoma patients. We evaluated the effect of anti-PD-1 Ab delivered
intravenously in glioblastoma-bearing wild-type mice and in the CD8 KO background and found therapeutic
benefit even in the absence of the CD8 effector T cell. Both peripheral monocyte-derived macrophages and
resident microglia were reduced within the glioblastoma microenvironment in mice treated with the anti-PD-1 Ab.
As such, our overall study hypothesis is that anti-PD-1 exerts therapeutic immune modulatory effects against
glioblastoma through innate immunity in the central nervous system (CNS). This proposal will address multiple
crucial questions to the field including: 1) Does the anti-PD-1 Ab cross into the CNS to exert a therapeutic effect;
2) what immune cells, other than the CD8 T cell, are contributing to the therapeutic effect of this agent; 3) are
the immune cells that are mediating the therapeutic effect arising from the periphery or are they intrinsic to the
CNS; and 4) how does the glioblastoma immune microenvironment change in response to treatment? To
address these questions, we will use contemporary murine models of glioma that closely approximate human
glioblastoma and manipulate both the innate and adaptive immune systems to dissect the impact and importance
of each in the context of anti-PD-1 treatment. Validation will be carried out using data from human subjects
treated with anti-PD-1. By clarifying the mechanistic role of anti-PD-1 therapeutic activity, we may identify the
subset of glioblastoma patients that are capable of responding to this type of strategy. This is a significant area
of unmet need if glioblastoma patients are to benefit from immunotherapy. These studies may also reveal that
anti-PD-1 treatment has a dual role on both the innate and adaptive immune system and when one arm is not
operational this agent toggles its modulatory properties to the dominant immune arm.

## Key facts

- **NIH application ID:** 10683098
- **Project number:** 5R01CA120813-15
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Amy Beth Heimberger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $287,999
- **Award type:** 5
- **Project period:** 2007-01-10 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683098

## Citation

> US National Institutes of Health, RePORTER application 10683098, Modulation of Microglia and T Cell Interactions in Malignant Glioma (5R01CA120813-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10683098. Licensed CC0.

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