# ITIM-receptors for cancer treatment

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $565,597

## Abstract

Abstract
T cell-centered immunotherapies, including PD-1/PD-L1 blockade, have been successful
in treating some types of cancers but not others. The roles of other immune cells including
immunosuppressive monocytic cells in tumor development and treatment are not well
defined. A better understanding of the molecular regulation of signaling and function of
these monocytic cells will support development of novel therapeutic strategies for cancer
treatment. The leukocyte Ig-like receptor subfamily B (LILRB) proteins are a group of type
I transmembrane glycoproteins with extracellular Ig-like domains that bind ligands and
intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that can recruit
tyrosine phosphatases SHP1, SHP2, or the inositol-phosphatase SHIP. We have been
investigating the roles of this family of immune checkpoint receptors in tumor
development. We demonstrated that several ITIM-receptors including LILRB2, LILRB4,
and a related receptor LAIR1 support leukemia development. As the most restrictively
expressed member of the LILRB family, LILRB4 is mainly expressed on monocytic cells
but not on stem cells or progenitors. We and others further demonstrated that LILRB4 is
a surface marker for monocytic AML and monocytic myeloid-derived suppressor cells.
Importantly, we elucidated two novel functions of LILRB4: it supports infiltration of
malignant monocytic cells and relieves immune inhibition of T cells. Furthermore, we
developed anti-LILRB4 blocking antibodies and CAR-T cells that efficiently inhibit
monocytic leukemia development in various mouse models including humanized and
patient-derived xenografted mice. Here, based on new preliminary results, we propose the
following Aims to test the hypothesis that the expression and signaling of LILRB4 in
immunosuppressive monocytic cells support tumor development. In Aim 1, we will
determine the function of LILRB4 signaling in immunosupressive monocytic cells and
whether LILRB4 blocking/targeting inhibits tumor development. We will then determine
how LILRB4 expression is transcriptionally regulated by extrinsic factors in Aim 2. Finally
we will determine whether the DNA sensor protein Absent In Melanoma 2 (AIM2) is a key
downstream effector of LILRB4 signaling in Aim 3. Our study will provide important
mechanistic insights into immune checkpoint biology and directly guide the development
of novel immunotherapies for cancer treatment.

## Key facts

- **NIH application ID:** 10360629
- **Project number:** 5R01CA248736-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** CHENGCHENG ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $565,597
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360629

## Citation

> US National Institutes of Health, RePORTER application 10360629, ITIM-receptors for cancer treatment (5R01CA248736-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10360629. Licensed CC0.

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