# Project 3: Role of Coinhibitory receptors in regulating Immune Tolerance in the Human Brain

> **NIH NIH P01** · YALE UNIVERSITY · 2023 · $628,125

## Abstract

Studies from our PPG have elucidated fundamental roles for PD-1/PD-L1 and TIGIT/CD155 in regulating
immune tolerance in cancer and autoimmunity. Our investigations in experimental models and in humans
suggest there are distinct effects of PD-1/PD-L1 and TIGIT/CD155 signaling in human Tregs with PD-1:PD-L1
interactions regulating T cell tolerance while TIGIT exhibits T cell intrinsic inhibitory effects that regulates
tolerance and Treg function. Based on single-cell transcriptomic and TCR sequence analyses of tumor samples
from brain tissue of patients with glioblastoma receiving PD-1 or combinations PD-1/TIGIT mAb, we
observed that while PD-1 blockade alone induced Treg proliferation, the combination of PD-1 & TIGIT blockade
resulted in IFN-secreting Treg effectors which resemble dysfunctional Tregs in autoimmunity. Data from
Projects 1 & 2 showed that PD-1 blockade increases the frequency of TIGIT+ Tregs and when coupled with
TIGIT agonism, controlled pathogenic T cells ameliorating autoimmunity induced by PD-1 blockade.
Furthermore, combination PD-1 & TIGIT blockade increases pro-inflammatory signatures in PD-L1+ and CD155+
myeloid cells without impairing the efficacy of PD-1 blockade in controlling tumors. These data suggest that
TIGIT is a potential target for treating immune-related adverse events associated with PD-1 blockade. Our
underlying hypothesis is that signaling through PD-1/PD-L1 and TIGIT/CD155 are distinct but
synergistically coordinate Treg and myeloid cell function in a bidirectional fashion in autoimmunity and
cancer. Thus, the goal of this project is to identify key pathways induced by PD-1/TIGIT signaling in human
Tregs and PD-L1/CD155 signaling in human myeloid cells. To achieve these goals, we propose in aim 1 to
determine how the balance of PD-1+ and TIGIT+ signaling in human Tregs modulates peripheral tolerance in
health and disease states by elucidating key transcriptional pathways induced by PD-1 and/or TIGIT signaling
and blockade in dysfunctional MS Tregs compared with healthy Tregs. Using brain tissue from glioblastoma
patients in our clinical trial, we will identify the in vivo effects of PD-1 and/or TIGIT blockade on Treg phenotypes
and clonal expansion using single-cell sequencing and spatial multi-omic technologies. In aim 2, we will
determine how PD-L1+ and CD155+ signaling governs transcriptional signatures in myeloid cells by examining
how alterations in PD-L1/CD155 signaling modulates myeloid cell function in MS patients in vitro. Finally, we will
identify key transcriptional signatures induced in vivo by PD-L1+ and CD155+ agonist in glioblastoma generating
immune-brain cell interactomes based on transcriptional signatures, which will be confirmed using spatial multi-
omics. Findings from our study will guide the development of combination immune checkpoint therapies in
autoimmunity and cancer and potentially provide a means to effectively administer these therapies while
preventing complications of auto...

## Key facts

- **NIH application ID:** 10643435
- **Project number:** 2P01AI039671-25
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** David A. Hafler
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $628,125
- **Award type:** 2
- **Project period:** 1997-09-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10643435

## Citation

> US National Institutes of Health, RePORTER application 10643435, Project 3: Role of Coinhibitory receptors in regulating Immune Tolerance in the Human Brain (2P01AI039671-25). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10643435. Licensed CC0.

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