# The Role of Mutant p53 in Regulating T-cell Immune Evasion in Pancreatic Adenocarcinoma and Other Cancers

> **NIH NIH F30** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $33,541

## Abstract

Project Summary/Abstract
 Harnessing a patient’s immune system by attenuating endogenous immune checkpoints on T-cells has
led to dramatic, durable tumor rejection for multiple tumor types. Nonetheless, pancreatic ductal adenocarcinoma
(PDAC) remains largely resistant to all therapies, including immunotherapies, leading to its notoriety as one of
the most lethal malignancies, with a 6% 5-year survival rate. To design efficacious treatments for PDAC, it is
important to understand the mechanism by which PDAC escapes the host immune system. Unlike
immunotherapy-responsive tumor types such as melanoma, PDAC is mutationally homogeneous, with up to
75% of tumors possessing mutations in the tumor suppressor p53. p53 loss is well-described to mediate tumor
escape from apoptosis and senescence. p53 missense mutants (mtp53) also acquire gain-of-function activities
distinct from p53’s wild-type activity. Pre-clinical studies support that mtp53 mediate tumor escape from immune
surveillance by modulating innate immune effectors, including NK cells and macrophages. Few studies have
been completed, however, investigating the role of mtp53 in altering adaptive immune effectors, including
cytotoxic T-cells. Understanding the role of mtp53 in mediating T-cell infiltration and function in PDAC would
provide a novel framework to understand and overcome resistance to cancer immunotherapy. In this project, I
will determine whether various structure-function classes of mtp53 impact PDAC oncogenesis or tumor
maintenance by impacting T-cell function. I hypothesize that p53 mutations mediate evasion of T-cell-
mediated killing and immunotherapy in PDAC and other tumors, and that mtp53 class is an important
factor in this process. To test this hypothesis, I will establish whether p53 tumor mutational status influences
T-cell infiltration, phenotype, and functionality in PDAC, using novel PDAC murine models and flow cytometry,
CyTOF, Caspase, and cytokine secretion assays, and determine whether p53 mutational status impacts
response to immune checkpoint inhibitors. With the successful completion of these aims, I will ascertain if p53
mutational status promotes T-cell-mediated immune escape in PDAC. These results would elucidate the role of
mtp53 activating mutations in tumorigenesis, identify potentially-targetable downstream effectors unique to
mtp53, and provide rationale to investigate mtp53 immune-regulation in PDAC and other tumor types.

## Key facts

- **NIH application ID:** 10189491
- **Project number:** 5F30CA228258-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Deborah Ann Silverman
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,541
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189491

## Citation

> US National Institutes of Health, RePORTER application 10189491, The Role of Mutant p53 in Regulating T-cell Immune Evasion in Pancreatic Adenocarcinoma and Other Cancers (5F30CA228258-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189491. Licensed CC0.

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