# Immune Regulation of Lung Squamous Metastasis

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $392,837

## Abstract

Project Summary:
Lung cancer is the leading cause of cancer-related deaths in the U.S., accounting for 158,040 deaths in 2015.
While targeted therapies of lung adenocarcinoma have improved overall survival, similar advances in lung
squamous carcinoma (LUSC) have been stagnant. Extensive molecular profiling through the Cancer Genome
Atlas (TCGA) effort revealed that LUSC tumors are highly idiosyncratic and rarely driven by solitary actionable
pathways. However, the tumor microenvironment (TME), which promotes the metastasis that accounts for 90
percent of cancer-related deaths, remains an attractive target for immune-based therapies. Recently, the
blockade of immune checkpoints with anti-Programed cell death protein 1 (PD1) antibodies has demonstrated
remarkable therapeutic promise in LUSC patients, with about 20% of unselected patients experiencing durable
responses. Thus, a more complete understanding of how the tumor microenvironment (TME) promotes LUSC
will allow us to build upon these advances. Using updated TCGA data for LUSC, we have uncovered a
previously unidentified subset of LUSC characterized by infiltration of inflammatory monocytes (IMs). This
subset accounts for nearly half of all LUSC patients, is associated with very poor outcome, and has numerous
signatures of immune evasion. Using immune-competent metastasis models of LUSC developed in our lab, we
have found that the CCL2-CCR2 axis is highly associated with IM recruitment and promotion of LUSC
metastasis. Although studies in other cancer types have revealed IMs differentiate into tumor-associated
macrophages (TAMs), which in turn leads to increased angiogenesis and invasiveness, very little is known
about the direct role of IMs on LUSC growth and metastasis. Taken together, we hypothesize that specific
molecular processes (i) recruit IMs into the LUSC tumor microenvironment, which (ii) directly promotes LUSC
tumor growth and development of distant metastasis, and (iii) interruption of the CCL2-CCR2 axis will
therapeutically inhibit these processes. In Aim 1, we will determine and characterize the upstream molecular
drivers responsible for IM recruitment into the LUSC microenvironment. In Aim 2, we will determine the direct
role of IMs in promoting LUSC tumor growth and metastasis. In Aim 3, we will evaluate the therapeutic efficacy
of targeting IMs in immune-competent metastasis models of LUSC, and whether this therapeutic approach is
synergistic in combination with anti-PD1 immune checkpoint inhibitors. Thus, taken together, our proposal aims
to uncover the molecular underpinnings that promote IM infiltration into the LUSC TME, define the mechanisms
by which this promotes LUSC progression, and to develop novel therapeutic strategies to interrupt these
processes.

## Key facts

- **NIH application ID:** 9999462
- **Project number:** 5R01CA215075-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Chad V Pecot
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,837
- **Award type:** 5
- **Project period:** 2017-09-21 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999462

## Citation

> US National Institutes of Health, RePORTER application 9999462, Immune Regulation of Lung Squamous Metastasis (5R01CA215075-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999462. Licensed CC0.

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