# Evaluation of T follicular regulatory cells as novel cellular targets of cancer immunotherapy

> **NIH NIH R37** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2023 · $102,450

## Abstract

Project Summary
Immune checkpoint blockade (ICB) targeting CTLA-4 or PD-1 rapidly assumed its role as a standard treatment
for solid tumors and can lead to dramatic, long-lasting responses; nonetheless, fewer than 30% of patients
respond to monotherapy with either agent. Combination therapy results in better long-term survival outcomes,
but also causes more frequent and severe immune-related adverse events (irAEs). Several novel
immunotherapies are currently being explored to evaluate their anti-tumor capacity. Crucially however, most of
these targets suffer from on-target, off-cell effects, as other immune cell types can express high levels of these
molecules. Hence, as low overall response rates, off-cell effects and widespread immune related toxicity severely
limit both treatment efficacy and monotherapy and combination therapy options, there is urgent need to develop
novel immunotherapy targets that exhibit a more restricted expression profile. We have recently demonstrated
that PD-1+ follicular regulatory T (TFR) cells were prevalent in tumor tissues of several cancer types in humans
and mice, and that they were critical cellular determinants of anti-PD-1 treatment efficacy. TFR cells were primarily
located within tertiary lymphoid structures (TLS) and exhibited superior suppressive capacity and in vivo
persistence when compared to regulatory T (TREG) cells, suggesting a key role for TFR cells in impairing patient
survival and impeding immunotherapy treatment efficacy. While we have shown that intratumoral TFR cells derive
from TREG precursor cells, the mechanisms and transcription factors (TFs) that are driving this differentiation step
are largely unknown. In Aim1, we propose to employ single-cell RNA-seq, single-cell ATAC-seq and micro-
scaled ChIP assays to fully characterize the transcriptomic signatures of tumor-infiltrating TREG cells, transitioning
(4-1BB+) TREG cells and TFR cells. Elucidating the enhancer profiles in different developmental stages of TREG to
TFR differentiation is likely to provide crucial insights into the TFs that instruct this differentiation step. These
analyses will define genes and TFs that are pivotal for the heightened suppressive capacity of TFR cells, as well
as for their maintenance or differentiation. Strategies to deplete TREG cells or to curb their functionality with the
aim of enhancing anti-tumor immunity are being intensively investigated. Crucially however, most of these
approaches are based on antibodies (i.e., ADCC-optimized for TREG cell depletion; i.e. anti-CTLA-4), which have
an inherently long half-life in vivo, thus increasing the likelihood of causing irAEs. Conversely, our data imply that
alternative dosing regimens of Phosphoinositide 3-kinase δ (PI3Kδ) inhibitors might offer a pathway to target TFR
cells more specifically. We propose that PI3Kδ represents a novel and appealing immunotherapy target in solid
tumors. In Aim 2 and Aim 3, we will assess whether alternative dosing regimens of...

## Key facts

- **NIH application ID:** 10737557
- **Project number:** 1R37CA276779-01A1
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Simon Eschweiler
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $102,450
- **Award type:** 1
- **Project period:** 2023-07-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10737557

## Citation

> US National Institutes of Health, RePORTER application 10737557, Evaluation of T follicular regulatory cells as novel cellular targets of cancer immunotherapy (1R37CA276779-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10737557. Licensed CC0.

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