# Targeting the Major Histocompatibility Class I-LILRB1 signaling axis for cancer immunotherapy by macrophages

> **NIH NIH F30** · STANFORD UNIVERSITY · 2020 · $29,275

## Abstract

PROJECT SUMMARY/ABSTRACT
Exciting progress in the field of cancer immunotherapy has generated tremendous interest in identifying new
immunotherapeutic targets, with particular interest in those focused on activating macrophages against cancer.
During cancer progression, malignant cells evade elimination by macrophages through the expression of “don't
eat me” signals, which inhibit phagocytosis by engaging inhibitory receptors on macrophages. One such anti-
phagocytic mechanism involves the expression of CD47, which effectively shields cancer cells from
macrophage-mediated clearance through interaction with the inhibitory macrophage receptor, SIRPα.
Therapeutic strategies blocking CD47-SIRPα signaling have demonstrated great promise in pre-clinical studies
for several cancers. Recent exciting progress has led to the discovery of a second “don't eat me” signaling axis
that involves MHC class I (MHC I) expressed by cancer cells, and the inhibitory macrophage receptor, LILRB1.
Antagonism of MHC I-LILRB1 signaling has shown potential as an effective strategy to promote tumor
clearance by augmenting phagocytosis of cancer cells. However, further preclinical studies are warranted to
evaluate the efficacy of LILRB1 blockade as an anti-cancer therapy. The initial goal of this proposal is to
enhance the knowledge of LILRB1 as an innate immune checkpoint molecule that can be targeted in cancer by
1) profiling LILRB1 expression within tumors and assessing the response to LILRB1 blockade in phagocytosis
assays with primary tumor-associated macrophages (Aim 1) and 2) testing combination clinical strategies to
amplify both macrophage and T-cell mediated tumor clearance (Aim 2). Lastly, this proposal aims to identify
additional “don't eat me” signals employed by human cancers that inhibit macrophage-mediated clearance. By
leveraging the knowledge of established innate immune checkpoints, a list of 90 candidate genes with high
likelihood to modulate the macrophage-mediated anti-tumor immune response has been compiled. The
proposed work involves the implementation of a novel CRISPR/Cas9 genetic screening pipeline against this
small pool of genes to identify additional “don't eat me” signals which can be blocked therapeutically to
augment macrophage-mediated cancer clearance (Aim 3). The accomplishment of the proposed aims will
provide valuable insight into how to develop clinical approaches that maximize both the innate and adaptive
immune responses to cancer.

## Key facts

- **NIH application ID:** 9999531
- **Project number:** 5F30CA232472-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Amira Barkal
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $29,275
- **Award type:** 5
- **Project period:** 2018-08-29 → 2021-08-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999531

## Citation

> US National Institutes of Health, RePORTER application 9999531, Targeting the Major Histocompatibility Class I-LILRB1 signaling axis for cancer immunotherapy by macrophages (5F30CA232472-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9999531. Licensed CC0.

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