# PD-L1 Intracellular RNA binding function regulates immune suppression

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $363,713

## Abstract

PROJECT DESCRIPTION/ABSTRACT
Programmed death ligand 1 (PD-L1), which promotes immune escape, is overexpressed in triple negative breast
cancer (TNBC), an aggressive subtype of breast cancer characterized by poor prognosis. Clinically approved
PD-L1 antibodies augment anti-tumor immunity by blocking extracellular PD-1/PD-L1 binding. However, the
contribution of intracellular PD-L1 to anti-tumor immunity and therapeutic resistance has remained poorly
understood. We have discovered a novel role for intracellular PD-L1 as an RNA binding protein that promotes
the stability of target RNAs. This new intracellular PD-L1 function in regulating RNA expression was independent
of the established extracellular role of PD-L1 as the ligand for PD-1. The activity of the anti-tumor immune
response is governed by a balance between immune effector cells and immune suppressor cells. Regulatory T
cells (Tregs) are a CD4+ T cell subpopulation that inhibit effector cell activity, suppress anti-tumor immunity and
promote therapeutic resistance. A hallmark of Tregs is the expression of the transcription factor, Foxp3, which
binds to the promoters of genes that support Treg activity. Foxp1 is a closely related family member of Foxp3.
Emerging data has demonstrated that Foxp1 cooperates with Foxp3 to encourage Foxp3-mediated transcription
and Treg function by maintaining Foxp3 occupancy at promoters of target genes. In our preliminary data, we
have identified Foxp1 as a key PD-L1 target RNA. We have found that the PD-L1 cytoplasmic domain, but not
the PD-L1 extracellular domain, interacts with Foxp1 RNA and promotes Foxp1 expression. In addition, we have
discovered that intracellular PD-L1’s promotion of Foxp1 expression is necessary for proper Treg differentiation,
Treg function, and TNBC progression. The Akt-mammalian target of rapamycin (mTOR) pathway regulates
metabolic reprogramming for proper T cell maturation and function. Our preliminary data suggests that PD-L1
and Foxp1 are required for proper Akt-mTOR pathway activation and metabolism specifically in Tregs, but not
effector T cells, suggesting that targeting the PD-L1-Foxp1 pathway may preferentially inhibit Tregs to address
therapeutic resistance. Our overarching hypothesis is that intracellular PD-L1 stabilizes Foxp1 RNA to
promote Treg immunosuppressive activity and therapeutic resistance. Further, inhibiting intracellular
PD-L1 will promote anti-TNBC immunity by blocking Treg activity. This hypothesis will be tested in a series
of three aims: Aim 1 will determine the influence of intracellular PD-L1 on Foxp1 mRNA stability and Treg
differentiation; Aim 2 will determine the effect of intracellular PD-L1 on Treg function; Aim 3 will compare
intracellular PD-L1 and extracellular PD-L1/PD-1 directed TNBC therapy. Clear delineation of the impact of
intracellular PD-L1 on cancer therapy will provide important insight for optimizing combination strategies aimed
at overcoming immune escape and therapeutic resistanc...

## Key facts

- **NIH application ID:** 10272518
- **Project number:** 1R01CA261932-01
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Robert W. Mutter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $363,713
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10272518

## Citation

> US National Institutes of Health, RePORTER application 10272518, PD-L1 Intracellular RNA binding function regulates immune suppression (1R01CA261932-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10272518. Licensed CC0.

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