# Identifying the Role of Tumor Cell Intrinsic DNMT1 in Anti-Tumor Immunity in Pancreatic Ductal Adenocarcinoma

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2022 · $51,752

## Abstract

Project Summary
 Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related death
in the United States. The five-year survival rate of less than nine percent is attributed mainly to a difficulty in
early detection and a lack of effective treatments for PDAC. Novel immunotherapies such as immune
checkpoint blockade which have revolutionized treatment of other cancers have failed to achieve efficacy in
PDAC. This is thought to be due to the immunosuppressive microenvironment of PDAC which limits the
effector T cell infiltration and activation necessary for effective immunotherapy. Understanding how to increase
T cell activation and infiltration despite an immunosuppressive microenvironment is essential to increasing the
efficacy of immunotherapies in PDAC.
 Using a genetically engineered mouse model (“KPCY”) of pancreatic cancer, our lab has demonstrated
that clones derived from primary KPCY tumors can be divided into “T-cell-inflamed” or “non-T-cell-inflamed”
phenotypes. While T-cell-inflamed tumors are responsive to combination immunotherapy, non-T-cell-inflamed
tumors are resistant. A CRISPR screen of non-T-cell-inflamed cells found that DNMT1, a DNA
methyltransferase involved in maintaining methylation marks through DNA replication, is important for tumor
growth in PDAC. Knockout of DNMT1 in a non-T-cell-inflamed tumor line was found to significantly increase T
cell infiltration and decrease tumor growth in vivo. T cell depletion, however, was found to rescue the wild type
phenotype. Based on recent studies of the non-specific DNMT inhibitor azacytidine, loss of DNMT1 is
hypothesized to de-repress endogenous retroviruses in the genome, leading to dsRNA induction which
activates a “viral mimicry” immune mechanism. The goals of this proposal are: (1) to determine how loss of
DNMT1 promotes T-cell dependent anti-tumor immunity, and (2) to assess the therapeutic potential of
targeting DNMT1 in conjunction with immunotherapy.
 To examine the mechanism of tumor cell intrinsic DNMT1 in inhibition of T-cell dependent suppression
of tumor growth, I will first assess the changes in DNA methylation at endogenous retroviruses and genes
related to the viral mimicry pathway provoked by loss of DNMT1. I will then determine if loss of DNMT1 leads
to activation of the viral mimicry pathway, and whether inhibition of this pathway rescues the wild type
phenotype (Aim 1). To determine the translational potential of DNMT1 as a target, I will first identify anti-tumor
changes in T cells and tumor cells provoked by loss of DNMT1. I will trial immunotherapy in mice with DNMT1
knockout tumors to determine changes in sensitivity to immunotherapy (Aim 2). Ultimately, the insights gained
from this study will provide us with a better understanding of the role of DNMT1 in regulating the PDAC
immune microenvironment and its potential as a therapeutic target.

## Key facts

- **NIH application ID:** 10379946
- **Project number:** 5F30CA260944-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Erin Elizabeth Hollander
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2021-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379946

## Citation

> US National Institutes of Health, RePORTER application 10379946, Identifying the Role of Tumor Cell Intrinsic DNMT1 in Anti-Tumor Immunity in Pancreatic Ductal Adenocarcinoma (5F30CA260944-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10379946. Licensed CC0.

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