# Targeting TREM2 to boost anti-cancer therapy

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $432,265

## Abstract

PROJECT SUMMARY
Cancer is a leading cause of death and disease. The recent success of immune checkpoint therapy (ICT) has
revolutionized tumor therapy, indicating that manipulation of the immune system is an effective strategy to treat
cancer. MAbs inhibiting CTLA-4 and PD-1 have been extensively shown to unleash T cell effector functions to
control tumors in both mice and some cancer patients. However, ICT is incompletely effective for certain tumors,
which escape using multiple mechanisms, one of which is the generation of a tumor microenvironment rich in
immunosuppressive myeloid cells. TREM2 is an immune receptor expressed by tissue macrophages that binds
phospholipids and lipoproteins and transmits intracellular signals through the ITAM pathway. Recently,
TREM2+ macrophages have been reported in many human tumors. In our preliminary data, we demonstrate that
TREM2-deficiency or mouse TREM2 blockade with the mAb 178 curbs subcutaneous tumor growth of the 3-
methylcholanthrene (MCA) cell line and leads to complete tumor regression when associated with suboptimal
PD-1 immunotherapy. Furthermore, high-resolution analysis of the tumor cell infiltrate in the MCA model reveals
complex remodeling of the myeloid cell landscape in Trem2–/– and anti-TREM2 treated mice. The overall goal of
this application is to advance our understanding of the therapeutic impact of TREM2 blockade in mouse models
and human cancer. In Aim 1 we show that TREM2 targeting enhances ICT mediated by anti-PD1; we propose
to determine whether TREM2 deficiency or blockade impact other tumor therapies, such as anti-CTLA4 and
chemotherapy, which elicit different types of immune responses. The impact of TREM2 will be assessed using
injected MCA cell lines and the spontaneous MMTV-PyMT model of breast cancer. In Aim 2 we will define the
mechanisms through which anti-TREM2 impacts the tumor microenvironment. Given that a) immunosuppressive
macrophages depend on lipid metabolism and accumulate lipid droplets; b) TREM2 promotes foam cell formation
by binding lipoproteins; and c) anti-TREM2 mAb blocks lipid binding to TREM2, we will test the hypothesis that
TREM2 blockade converts tumor macrophages from immunosuppressive to immunostimulatory by blocking lipid
droplet accumulation and foam cell formation. We will also test an alternative mechanism based on the
observation that TREM2 is cleaved from the cell surface by ADAM metalloproteases, generating soluble TREM2
(sTREM2), which promotes survival of macrophages in various disease models. We will test the hypothesis that
lack of sTREM2 in a transgenic mouse with uncleavable TREM2 prevents survival of immunosuppressive tumor
macrophages. In Aim 3, we show unpublished data indicating that anti-human TREM2 mAb 21E10 delays tumor
growth of an injected MCA cell line in mice expressing human TREM2 in place of mouse TREM2. Therefore, we
will determine whether TREM2 blockade with a specific mAb can be extended to a preclinical model expressing
t...

## Key facts

- **NIH application ID:** 10477296
- **Project number:** 5R01CA262684-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MARCO COLONNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $432,265
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477296

## Citation

> US National Institutes of Health, RePORTER application 10477296, Targeting TREM2 to boost anti-cancer therapy (5R01CA262684-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10477296. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*