# Role of YAP in Treg Function and YAP Targeting for Cancer Immunotherapy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $369,912

## Abstract

Background: Foxp3+CD4+CD25+ regulatory T cells (Treg)-mediated immune suppression is crucial for
immune evasion by tumor cells and an obstacle for successful tumor immunotherapy. Hence, the ability to
disrupt Treg function is of major therapeutic significance. Although Foxp3 is a master regulator of Treg, Foxp3
expression is not sufficient to account for the suppressive capacity of Tregs. It has been suggested that Foxp3
needs to associate with other co-factors in order to suppress non-Treg (T effector) genes and enforce Treg
associated gene expression and function. Recently, we found that Yes-associated protein (YAP), a
downstream co-activator of the Hippo pathway, is highly expressed by Tregs and is critical for Foxp3-mediated
suppressive activity. Furthermore, T cell specific YAP knockout mice mount superior immune responses to
implanted B16 melanomas. We hypothesize that YAP is an attractive target for immunotherapeutic
strategies aimed at breaking tolerance and enhancing anti-tumor immunity in the cancer setting.
Specific Aims: In the current proposal, we are seeking to: 1) Further dissect the molecular mechanisms by
which YAP facilitates Foxp3+ Treg function; 2) Understand the consequences of YAP deletion for Treg cell
differentiation and function; and 3) Explore the anti-tumor efficacy of YAP inhibitor(s) alone or in combination
with immune checkpoint blockade.
Objectives & Significance: These studies will expand our understanding of the mechanisms behind YAP
facilitates Foxp3 regulation and Treg function. In so doing we will further dissect the molecular mechanism by
which YAP facilitates Foxp3-mediated Treg function. Furthermore, we will explore Yap as a potential novel
therapeutic target by pharmacologically manipulating YAP activity, and testing various inhibitors for efficacy as
breakers of immune tolerance, which is a major obstacle for anti-cancer immunotherapy. The use of such Yap
inhibitors in combination with other immune modulators such as anti-PD-1 is expected to improve the
effectiveness of immunotherapy, and boost anti-tumor immunity and patient survival.
Methodology: In these studies we will deploy biochemical, molecular biology, genetic and bioinformatic
approaches to further dissect the role of YAP in Treg cell biology, and attempt to discover known and novel
inhibitors of Yap that are effective alone and synergistic with immunotherapies in reducing tumor burden. Both
novel and known YAP inhibitors will be tested for their capacity to undermine Treg function and break immune
tolerance in vitro and in vivo.
Expected Results & Implications: Our experiments will reveal a novel role of YAP in Treg cell function. We
predict that a detailed understanding of the physiological role of YAP induction and its impact on Foxp3 and
Treg function will provide insight into therapeutic targeting of this pathway. The use of YAP inhibitors in
combination with proven checkpoint targeting agents may yield even better anti-tumor efficacy.

## Key facts

- **NIH application ID:** 9817686
- **Project number:** 5R01CA218270-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** DREW M. PARDOLL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $369,912
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9817686

## Citation

> US National Institutes of Health, RePORTER application 9817686, Role of YAP in Treg Function and YAP Targeting for Cancer Immunotherapy (5R01CA218270-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9817686. Licensed CC0.

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