# PTEN, Tregs and MDSCs in the tumor microenvironment

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $347,700

## Abstract

Tumors express many immunogenic antigens, but in most cases the spontaneous response to these antigens
by host T cells is poor. This represents a major problem for both immunotherapy and immunogenic
chemotherapy. We now describe a population of highly immunogenic dendritic cells (DCs), arising in tumors
during immunotherapy, which share attributes of “conventional” CD103+ cDCs, but which also express
lineage-markers of monocytic MDSCs. The scientific premise of the proposal is that this population of “dual-
phenotype” Ly6c+/CD103+ DCs is critical to anti-tumor immune responses during immunotherapy, and that it is
possible to therapeutically amplify and increase these cells so as to markedly enhance the effect of
immunotherapy. Aim 1 will test the hypothesis that the Ly6c+/CD103+ DCs arise via rapid differentiation of
immature myeloid cells (monocytic MDSCs) in the tumor milieu, via a pathway that requires re-activation of
classical DC-lineage transcription factors. The signal that initially drives this differentiation step is inflammation
from dying tumor cells, but this is then rapidly amplified by inflammatory signals from activated T cells (positive
feedback loop). The hypothesis predicts that Ly6c+/CD103+ DCs are critical for anti-tumor immune responses
because they are the only cells in the tumor capable of re-activating anergic/exhausted T cells. Aim 2 will test
the hypothesis that the key mechanism controlling differentiation of Ly6c+/CD103+ DCs is the transcription
factor p53 expressed in MDSCs. The hypothesis predicts that p53 acts by inducing expression of the pro-
inflammatory transcription factor IRF5; and that the upstream signal for p53 activation is the cell-intrinsic
respiratory burst (reactive oxygen species) produced in response to inflammatory cytokines. Aim 3 will test the
translationally-relevant hypothesis that pharmacologic activation of the p53 pathway, using clinically-applicable
p53-agonist drugs, will drive the differentiation of increased numbers of Ly6c+/CD103+ DCs during
immunotherapy, thus markedly enhancing and prolonging the anti-tumor immune response. To support
translation of this approach to humans, this aim will also test the prediction that human myeloid DCs are
controlled by an analogous p53-driven, IRF5-dependent maturation pathway. The translational importance
of these findings is that they identify myeloid-lineage p53 as a previously unsuspected target for
immunotherapy, which can be targeted by existing p53-agonist drugs already under clinical development for
other indications.

## Key facts

- **NIH application ID:** 9962303
- **Project number:** 5R01CA211229-04
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** David H. Munn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,700
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962303

## Citation

> US National Institutes of Health, RePORTER application 9962303, PTEN, Tregs and MDSCs in the tumor microenvironment (5R01CA211229-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9962303. Licensed CC0.

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