# Mechanisms of B cell specific IL-35 expression in cancer.

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $27,917

## Abstract

Project Abstract
Pancreatic Ductal Adenocarcinoma (PDA) is the most commonly diagnosed form (~90%) of pancreatic cancer
with a dismal 5-year survival rate of ~8%. PDA features a prominent pro-tumorigenic microenvironment rich in
immunosuppressive cells that inhibit functions of anti-tumor immunity. Current immunotherapeutic approaches
have been unsuccessful in improving PDA patient outcomes, leaving a need for a better understanding of the
immunomodulatory signaling mechanisms within pancreatic tumor microenvironment. We have identified
infiltrating regulatory B cells as being key contributors to pancreatic tumorigenesis through their expression of
the regulatory cytokine IL-35, which directly inhibits anti-tumor immune responses. The mechanisms that cause
B cells to produce IL-35 in cancer and promote pancreatic tumor growth are not known. Using a mouse model
harboring a monoclonal fixed B cell receptor (BCR), or mice with a B cell-specific deletion of the Toll-Like
Receptor (TLR) adaptor protein MyD88, I found that orthotopically implanted pancreatic tumors were drastically
reduced in size as compared to WT mice. I have also conducted in vitro analysis of TLR and BCR activation and
found that co-stimulation of endosomal TLRs and the BCR leads to a robust increase of IL-35 expression in B
cells. Based on my preliminary data, I hypothesize that cancer-driven upregulation of IL-35 in B cells is dependent
on crosstalk between BCR and endosomal TLRs, which promotes pancreatic tumor growth through
immunosuppression. I propose two specific aims to test my hypothesis. In Aim 1, I will determine how BCR and
endosomal TLR signaling via Bruton's tyrosine kinase (BTK) contributes to expression of IL-35 expression in B
cells, using analysis of signaling pathways in primary regulatory B cells and established B cell lines. In Aim 2, I
will investigate how activation of both BCR and TLR signaling in B cells promotes PDA tumor growth in vivo. To
accomplish this task, I will analyze mouse models expressing a fixed BCR specificity with or without specific
antigen exposure, mouse models lacking MyD88 signaling in B cells, as well as a cross of the two models. Our
proposed research will provide an understanding of a previously uncharacterized facet of B cell-mediated
function in PDA and use state-of-the-art PDA murine models to test strategies that block immune suppressive
pathways. Ultimately, I anticipate my findings will reveal a targetable mechanism to inhibit B cell-mediated
immunosuppression in pancreatic tumors and provide a multi-faceted training experience to help advance my
scientific career.

## Key facts

- **NIH application ID:** 10084162
- **Project number:** 5F31CA239494-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Daniel E Michaud
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $27,917
- **Award type:** 5
- **Project period:** 2020-01-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084162

## Citation

> US National Institutes of Health, RePORTER application 10084162, Mechanisms of B cell specific IL-35 expression in cancer. (5F31CA239494-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10084162. Licensed CC0.

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