# PKC agonism restricts innate immune suppression and promotes antigen cross-presentation in Triple Negative Breast Cancer

> **NIH NIH F31** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $32,848

## Abstract

SUMMARY
Immune checkpoint blockade (ICB) has revolutionized cancer therapy showing unprecedented long-term
antitumor responses. However, most patients do not respond to ICB therapies due at least partly to
immunosuppression. Immunotherapy non-responders have high levels of circulating myeloid-derived suppressor
cells (MDSCs)- an immunosuppressive innate cell population that suppresses both innate and adaptive
immunity. Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancers with poor
responses to conventional therapies. TNBC patients harbor higher levels of MDSC populations compared to
non-TNBC patients. Consequently, TNBC and other solid tumor patients who have high levels of circulating
MDSCs respond poorly to ICB. Hence, strategies that reduce MDSC’s suppressive function while promoting
cross-priming of CD8+ T cells are likely to be effectively combined with ICB for a maximum therapeutic benefit.
Protein Kinase C (PKC) is a family of kinases composed of 11 isoforms that play a critical role in cell signaling.
PKC delta (PKC) is the most abundant isoform in myeloid cells and plays an important role in dendritic cell (DC)
function. To date, the role of PKC in myeloid cells in cancer is unknown. Using varied informatic approaches in
patient databases, I found that BC patients with both high expression of PRKCD and either high expression of
CD8+ T cell or low expression of MDSC gene signatures in tumors had a significantly greater overall survival
compared to other groups, suggesting support for activation of PKC. Novel preliminary data suggests that PKC
agonism using FDA-approved PEP005 and prostratin reduced MDSC generation from bone marrow progenitors
specifically via activation of PKC isoform. PKC agonism induced MDSC differentiation to CD103+ DC-like cells
both ex-vivo and in vivo. Additionally, PEP005-treated MDSCs lost their suppressive capacity on CD8+ T cells in
both in vitro and in vivo pilot suppression assays and efficiently cross-primed OT-I CD8+ T cells. Mechanistic
studies reveal transcription factor IRF5 as a potential target of PKC-to be explored in this proposal. Based on
rigorously generated pilot data, I hypothesize that PKC agonism combined with agonistic CD40 mAb will
sensitize TNBC tumors to ICB through induced differentiation of MDSCs to DC-like cells via activation of PKC
and its downstream target IRF5. CD40 is mainly expressed by myeloid cells and its activation has been shown
to effectively activate antigen-presenting cells. Aim 1 & 2 will determine if PKC activation controls MDSC and
DC phenotype and function and will determine to what extent pharmacologic activation of PKC in combination
with agonistic CD40 mAb improves anti-PD-L1 therapy in TNBC mouse models. The proposed training will
prepare me for my long-term goal of becoming a tumor immunologist with a research objective to develop novel
immunomodulatory therapeutic approaches against solid tumors as an independent investigato...

## Key facts

- **NIH application ID:** 10387395
- **Project number:** 1F31CA268871-01
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Mehdi  Chaib
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $32,848
- **Award type:** 1
- **Project period:** 2021-12-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387395

## Citation

> US National Institutes of Health, RePORTER application 10387395, PKC agonism restricts innate immune suppression and promotes antigen cross-presentation in Triple Negative Breast Cancer (1F31CA268871-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10387395. Licensed CC0.

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