# PIKfyve regulation of IL-12 signaling in dendritic cells and cancer immunity

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $20,199

## Abstract

PROJECT SUMMARY/ABSTRACT
 Since the discovery of the IL-12 cytokine, it has been considered a “master regulator” of the immune
system. Primarily produced by dendritic cells, IL-12 is the key signaling molecule linking innate to adaptive
immunity to drive IFN𝛾𝛾/Th1-mediated T cell responses against pathogens and cancer. Preclinical studies have
long shown that enhancing IL-12 signaling improves vaccines. Recently, IL-12 in dendritic cells was shown to
be required for anti-PD1 efficacy in mouse models of cancer. Despite the data nominating the IL-12 pathway
as a therapeutic target in cancer, previous attempts to directly administer IL-12 in clinical trials have resulted in
patient death from cytotoxic response or poor efficacy due to IL-10-mediated negative feedback. Subsequent
efforts in cancer have largely focused on improving methods to deliver and release IL-12 with limited success.
Therefore, there is a significant need to better understand the biology of IL-12 regulation in dendritic cells to
identify novel, safe and effective strategies of targeting this pathway as an anti-cancer strategy.
 Our group previously identified PIKfyve lipid kinase as a novel target of the highly efficacious, well-
tolerated and orally administered multi-kinase inhibitor, ESK981. We demonstrated the ability of this drug to
reduce tumor growth in multiple syngeneic mouse models of cancer and enhance anti-PD1 therapy.
Interestingly, drug efficacy was dependent on the presence of CD8+ T cells, and the IL-12 and IFN𝛾𝛾 and
signaling pathways in vivo. Furthermore, ESK981 could directly enhance IL-12 signaling in primary dendritic
cells in vitro and in vivo through transcriptional regulation of IL12B.
 Therefore, the overall goal of this project is to define the mechanism of IL-12 regulation by PIKfyve and
demonstrate the nature of PIKfyve inhibition, as an anti-cancer therapy, in anti-tumor immune responses. The
overarching hypothesis is that PIKfyve inhibition induces IL-12 signaling in dendritic cells to enhance antigen-
specific, CD8+ T cell responses in cancer. Experiments in Aim 1 will investigate the effect of Pikfyve
knockdown and conditional knock-out in mouse dendritic cells on the genes and protein subunits in the IL-12
signaling pathway in vitro and in vivo. To examine dendritic cell subsets, such as CD8α+ and CD103+ cDCs,
mice with genetic knock-out of Batf3 will be included for in vitro and in vivo studies. Experiments in Aim 2 will
study the potential anti-tumor effect of PIKfyve inhibitors, including ESK981and Apilimod, on dendritic cell
Pikfyve conditional knock-out, Batf3 knock-out, and wild type mice. We will monitor tumor progression and
examine T cell responses in the tumor draining lymph nodes and tumor microenvironment, including OVA
model antigen and neoantigen specific CD8+ T cell activation using tetramers available for the MC38 tumor
model. The proposed study will provide greater insight into the biology of IL-12 signaling in dendritic cells an...

## Key facts

- **NIH application ID:** 10451543
- **Project number:** 5F31CA264961-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jae Eun Choi
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $20,199
- **Award type:** 5
- **Project period:** 2021-08-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451543

## Citation

> US National Institutes of Health, RePORTER application 10451543, PIKfyve regulation of IL-12 signaling in dendritic cells and cancer immunity (5F31CA264961-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10451543. Licensed CC0.

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