# Targeting Dectin-2 on Tumor-associated Macrophages for the Treatment of Cancer

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $434,773

## Abstract

PROJECT SUMMARY/ABSTRACT
Background: Immunotherapy has emerged as one of the most promising approaches for the treatment of
cancer. Unfortunately, a large number of patients and common tumor types do not respond to existing
immunotherapies. Tumor-associated macrophages (TAMs), which accumulate in many cancers and suppress
anti-tumor immunity, likely contribute to this problem.
Hypothesis and Objective: Based on encouraging preliminary data, we hypothesize that engagement of
Dectin-2, a pattern recognition receptor that is highly expressed by TAMs in certain tumors, can reprogram
TAMs into potent antigen-presenting cells capable of inducing immunity against a wide range of cancers. Our
objective is to validate this hypothesis by analyzing the immunological and anti-tumor effects of natural and
synthetic Dectin-2 agonists in mouse models of cancer.
Specific Aims: Aim 1: Analyze the factors that regulate Dectin-2 expression and the mechanisms by which
Dectin-2 agonists reprogram TAMs and induce anti-tumor immunity. Aim 2: Assess the anti-tumor effects of
natural Dectin-2 agonists, alone and in combination with other agents, on a range of aggressive cancers. Aim
3: Synthesize glycopeptide agonists of Dectin-2 and assess their anti-tumor activity alone and in combination
with other agents. Aim 4: Construct tumor-targeted antibody-glycopeptide conjugates and evaluate their
functional and therapeutic effects.
Study Design and Methods: Since TAMs in some tumors express little or no Dectin-2, we will analyze the
effects of natural Dectin-2 agonists on TAMs in the presence of GM-CSF, which induces Dectin-2 expression.
The anti-tumor effects of the agonists will be studied in mouse models of pancreas, breast, colon, lung, and
skin cancer with a spectrum of Dectin-2 expression, both as monotherapies and in combination with GM-CSF
and other agents shown to enhance the efficacy of Dectin-2 agonists in our mouse models. Mass cytometry
and recently developed informatics tools will be utilized to analyze the effects of Dectin-2 ligands on the anti-
tumor immune response in multiple tissues. To generate more effective and clinically applicable therapies, a
novel synthetic approach will be used to produce compositionally defined Dectin-2 ligands that are optimized
for TAM activation. The most efficacious of these synthetic Dectin-2 ligands will be conjugated to tumor-
targeted antibodies for purposes of enhanced tumor delivery and TAM-mediated tumor cell killing, and their
safety and efficacy assessed.
Expected Results and Impact: We expect these experiments to demonstrate that engaging Dectin-2 on
TAMs induces immunity against a wide range of tumors, including tumors resistant to checkpoint blockade,
and that Dectin-2 agonists used alone or in combination with other anti-tumor agents can induce durable tumor
regression. The most promising of these agonists will be candidates for clinical development.

## Key facts

- **NIH application ID:** 10148554
- **Project number:** 5R01CA222969-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** EDGAR G. ENGLEMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $434,773
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148554

## Citation

> US National Institutes of Health, RePORTER application 10148554, Targeting Dectin-2 on Tumor-associated Macrophages for the Treatment of Cancer (5R01CA222969-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10148554. Licensed CC0.

---

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