# A novel immunotherapy for pancreatic cancer using micro-RNA-29a

> **NIH NIH F31** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $53,974

## Abstract

Project Summary
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States with a 5-year survival
rate of 12%. Despite the success of immune-modulating therapies such as immune checkpoint blockade (ICB)
in other cancers such as melanoma, single agent ICB is decidedly ineffective in pancreatic ductal
adenocarcinoma (PDAC), leaving surgery and palliative chemotherapy the only options for over 80% of patients.
CD8 T cells are the key effectors of anti-tumor immune responses that recognize and eliminate early malignant
cells and can enforce durable responses that prevent recurrence and metastatic spread through adaptive
immune memory. In PDAC, chronic exposure to cellular constituents in the tumor microenvironment (TME) leads
to the terminal dysfunction of CD8 T cells, termed “exhaustion”. Exhausted CD8 T cells (TEX) have reduced
proliferative capacity, an inability to persist and proliferate, and limited protective capacity compared to functional
CD8 T cells which is a major barrier to the success of immunotherapy in PDAC. Stelekati et. al. has recently
shown that antagonizing surface checkpoint molecules (such as PD-1) in chronic infection can synergize with
overexpression of one micro-RNA (miR), miR-29a, in CD8 T cells to abrogate TEX differentiation and restore
antigen-specific cytotoxicity and T cell memory In parallel, the Datta lab at UMMSM has recently uncovered TNF
signaling to drive T cell dysfunction in PDAC through a myeloid TNF-TNFR2 dependent manner. The goal of this
project is to determine the contribution of TNFR2-miR-29a to CD8 T cell dysfunction in PDAC to generate durable
T-cell mediated antitumor activity. I hypothesize that miR-29a regulates TEX differentiation by downregulating
immunosuppressive signaling and provides a promising intervention to overcome resistance to immune
checkpoint blockade in PDAC. Using the canonical KPC model of PDAC engineered to express the neoantigen
Ova, I retrovirally overexpress (OE) miR-29a in antigen-specific OT-1 CD8 T cells and observed improved tumor
clearance, along with altered phenotypic states. Consequently, in this project I aim to: (1) alter the differentiation
of terminally exhausted cells to a progenitor and memory-like phenotype that express Ly108, TCF-1, and CD127,
which has shown to be the subset responsive to a-PD-1 checkpoint blockade therapy. I will then validate the
translational importance of these findings by developing an effective combination strategy using miR-29a in mice;
(2) determine the precise contribution of myeloid-derived TNF-TNFR2 signaling upstream of terminal TEX
differentiation in the PDAC tumor microenvironment. By validating this novel mechanistic link between myeloid
immunosuppression and terminal T cell exhaustion, this work may uncover tolerogenic circuitries characteristic
of immunosuppressive TME’s such as PDAC. Taken together, this work will enhance our understanding of T cell
dysfunction in the PDAC TME and elucidate a nov...

## Key facts

- **NIH application ID:** 10997577
- **Project number:** 1F31CA294908-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Christine Isabelle Rafie
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997577

## Citation

> US National Institutes of Health, RePORTER application 10997577, A novel immunotherapy for pancreatic cancer using micro-RNA-29a (1F31CA294908-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997577. Licensed CC0.

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