# Investigating Macrophage Molecular and Functional Diversity in Tumor Immunity

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $684,604

## Abstract

PROJECT SUMMARY
 Macrophages (MF) are one of the largest immune cell components of tumor lesions, where their numbers
can even exceed cancer cells. MF play a key role in shaping the composition of the tumor microenvironment
(TME), the modulation of tumor innate and adaptive immunity, and the response to cancer immunotherapy.
Because of their critical roles, MF are an important target for cancer treatment. However, modulating tumor-
associated MF has proved extremely difficult. This is in large part because we still do not have a complete
understanding of the tumor MF compartment. In order to develop ways to modulate tumor MF and promote
cancer immunity, it is vital we gain a deeper understanding of the molecular and functional diversity of MF in
their tissue context.
 Using mass cytometry (CyTOF) and single cell RNA-seq (scRNA-seq), we initiated deep characterization of
the immune composition of early human non-small cell lung carcinomas (NSCLC). We uncovered evidence of
multiple distinct MF populations enriched in human tumors. Notably, related MF clusters were also identified in
mice lung cancer lesions. Using fate mapping and scRNA-seq, we discovered these discrete MF populations
differ in developmental origin and have a distinct distribution in the TME. When the different subsets of MF were
depleted, tumor growth was impaired, but the alterations in TME differed, suggesting distinct mechanisms of
activity. Based on our findings, we hypothesize that the unique subsets of MF have differential molecular states
and mediate differential contributions to tumor growth, organization, immunity, and response to PD1 blockade.
To address our hypothesis, we will: (1) comprehensively map the MF compartment of human lung tumors, at the
single cell level and with spatial resolution, at baseline and during treatment with PD1 blockade, in NSCLC
patients enrolled in a neoadjuvant immunotherapy clinical trial, (2) assess the functional contribution of distinct
MF subsets to tumor tissue remodeling and immune cell dynamics in the TME, and (3) determine the contribution
of distinct MF subsets to lung tumor immunity. We will also (4) investigate the function and activity of a specific
cell surface receptor, Trem2, which we found to be exclusively expressed on monocyte-derived MF in both
human and mouse lung tumors, and whose knockout impaired lung tumor growth similar to MF depletion;
suggesting an important and potentially targetable molecule in MF control of tumor growth.
 The outcome of these studies will (i) uncover the molecular and functional diversity of the MF compartment
of human lung tumors, (ii) determine how distinct MF subsets, and MF-specific genes, influence tumor growth,
the TME state, and tumor immunity, and (iii) provide insight into to how MF subsets influence, and are influenced
by, PD1 blockade in human NSCLC. These studies have the potential to help us understand some of the factors
that contribute to tumor response and resistance to immune ed...

## Key facts

- **NIH application ID:** 10335906
- **Project number:** 5R01CA254104-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Brian D Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $684,604
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10335906

## Citation

> US National Institutes of Health, RePORTER application 10335906, Investigating Macrophage Molecular and Functional Diversity in Tumor Immunity (5R01CA254104-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10335906. Licensed CC0.

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