# Biomaterial approaches to attenuate macrophage recognition of "self"-signals from cancer cells

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2020 · $67,446

## Abstract

Project Summary/Abstract
 In this project, two biomaterial approaches will be developed to investigate how macrophages are
reprogrammed by their microenvironment and to block the undesired consequences of this reprogramming.
Macrophages are capable of infiltrating solid tumors and can phagocytose cancer cells provided that inhibitory
“self”-signaling pathways are blocked and pro-phagocytic signals are present. This approach is the basis for a
recent adoptive cell transfer therapy using engineered bone marrow-derived macrophages (eMDMs) to treat
solid tumors. While this therapy was shown to be safe and effective at shrinking tumors in mouse models, further
improvements are required for successful translation. A major barrier that must be overcome is the relatively
rapid loss of the phagocytic ability of eMDMs and their acquisition of an M2-like phenotype that is similar to
tumor-associated macrophages. Macrophage reprogramming by the tumor microenvironment results in
increased expression of SIRPα, a cell surface receptor that recognizes the CD47 “marker of self” protein that is
overexpressed on many cancer cells. It is hypothesized here that increased SIRPα on reprogrammed
macrophages sensitizes them to CD47 on cancer cells and inhibits phagocytosis.
 In Aim 1, polymeric nanoparticles will be used to deliver small molecule drugs and microRNAs to eMDMs in
order to maintain a low SIRPα, phagocytic phenotype. Drug-loaded nanoparticles will be taken up by eMDMs
prior to their injection into tumor-bearing mice. Localized, sustained release of drugs that suppress SIRPα
expression is anticipated to prolong phagocytosis and to improve tumor shrinkage. In Aim 2, engineered
polyacrylamide hydrogels will be used to investigate how substrate stiffness acts a physical cue to regulate self-
signaling between macrophages and cancer cells through the CD47-SIRPα axis. Preliminary data suggest that
SIRPα expression increases on stiff substrates, providing a potential mechanism by which stiff tumor
microenvironments might reprogram macrophages and inhibit phagocytosis of cancer cells.
 Together, the approaches in Aims 1 and 2 demonstrate how biomaterials can be used to study and engineer
biology, specifically immune cells. Successful completion of these aims will have a significant translational impact
(i.e. the improvement of macrophage based therapies) and provide important new insights into cell biology and
mechanobiology (i.e. an understanding of how physical cues influence self-signaling in the innate immune
system). These aims are part of the Research Training Plan for my postdoctoral fellowship and provide the
opportunity for me to acquire both depth by enhancing my biomaterials skill set and breadth by developing new
expertise in cell biology, cancer biology, and immunology. This will position me for success in attaining my goal
of becoming an independent investigator working at the interface of these disciplines.

## Key facts

- **NIH application ID:** 9914098
- **Project number:** 5F32CA228285-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Lawrence J Dooling
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2018-06-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914098

## Citation

> US National Institutes of Health, RePORTER application 9914098, Biomaterial approaches to attenuate macrophage recognition of "self"-signals from cancer cells (5F32CA228285-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9914098. Licensed CC0.

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