# Function of IRF8 in T cell activation and immune tolerance

> **NIH NIH F30** · AUGUSTA UNIVERSITY · 2020 · $50,520

## Abstract

Project Summary
 Humans respond to tumor development by generating tumor-antigen-specific effector cytotoxic
lymphocytes (CTLs) to eliminate tumor growth and development. However, tumor cells often mount a
counterattack against CTLs by sensing activated T cell-produced IFNγ as a danger signal. In an “adaptive
immune resistance mechanism,” tumor cells up-regulate PD-L1, suppressing PD-1+ CTLs in the tumor
microenvironment. Therefore, tumor cells hijack the T cell-APC immune checkpoint system to evade host
cancer immunosurveillance. Accordingly, anti-PD-1 antibody immune checkpoint inhibitor (ICI)
immunotherapy has shown remarkable and durable efficacy in many types of human cancers. However,
factors underlying a robust response to ICI therapy remain unclear, and human colorectal cancer, except for
the small subset of microsatellite instable subtype cases (MSI), does not respond to ICI immunotherapy,
suggesting that other immune checkpoints may suppresses CTL activation in the CRC tumor
microenvironment. Interferon Regulatory Factor 8 (IRF8) was originally identified as a lineage-specific
transcription factor for myeloid cell differentiation. Loss of IRF8 expression leads to accumulation of
CD11b+Gr1+ immature myeloid cells in mice that phenotypically resemble myeloid-derived suppressor cells
(MDSCs). IRF8 has recently emerged as a key regulator of T cell activation. In preliminary studies, we
determined that IRF8 represses OPN expression in myeloid cells to regulate CD8+ T cell activation in a cell-
extrinsic manner. Our central hypothesis is that the CD44-OPN axis is another immune checkpoint and that
colon carcinoma cells overexpress OPN as a mechanism to suppress CTL activation in the tumor
microenvironment. Our objectives are: 1) elucidate the molecular mechanism underlying IRF8 regulation of
OPN expression in myeloid cells under physiological and pathological conditions; and 2) test the hypothesis
the tumor cell-expressed OPN engages CTL-expressed CD44 to suppress CTL activation in the tumor
microenvironment and to promote tumor progression. Successful completion of this project will not only
establish CD44-OPN as a novel immune checkpoint but will also provide the mechanistic basis for the
development of new therapies to overcome colorectal cancer resistance to immunotherapy.

## Key facts

- **NIH application ID:** 9841296
- **Project number:** 5F30CA236436-02
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** John David Klement
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-12-18 → 2022-12-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841296

## Citation

> US National Institutes of Health, RePORTER application 9841296, Function of IRF8 in T cell activation and immune tolerance (5F30CA236436-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841296. Licensed CC0.

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