# Project 1: Activating Phagocytic Macrophages in non-Hodgkin Lymphoma

> **NIH NIH P50** · UNIVERSITY OF IOWA · 2020 · $251,021

## Abstract

ABSTRACT – Project 1 
The mononuclear phagocyte system is critical in the host's response to pathogens and inflammation, but it is 
also critical for removing old or malignant cells. In non-Hodgkin lymphoma (NHL), monocytic cells are central 
components of the innate immune system and CD14+ monocytes in the peripheral blood as well as CD68+ 
tumor-associated macrophages (TAMs) in tissue influence the prognosis of patients. 
 We have previously shown that CD14+HLADRlow monocytes are increased in the peripheral blood of 
NHL patients, are induced by IL-10, and profoundly suppresses T-cell function. However, in lymphoma tissue 
biopsies, we found that many CD68+ TAMs downregulate CD14 expression. While CD14+ TAMs typically 
expressed common macrophage markers, we found that the CD68+CD14- fraction expressed very few of these 
markers. To determine whether CD68+CD14- TAMs retained macrophage function, we measured the 
expression of signal-regulatory protein α (SIRPα), a receptor that inhibits phagocytic function. Based on SIRPα 
expression, we identified 2 distinct populations of TAMs in sites involved by lymphoma – those that were 
CD14+SIRPαhigh and those that were CD14-SIRPαlow/- – but the phagocytic ability and role of these two 
populations is unknown. 
 SIRPα regulates macrophage-mediated removal of apoptotic cells that upregulate `eat-me' signals such 
as calreticulin. The induction of phagocytosis by `eat-me' signals on tumor cells is countered by `don't-eat-me' 
signals such as CD47, which binds macrophage SIRPα to inhibit phagocytosis. CD47 has been shown to be 
highly expressed on lymphoma cells and is a mechanism by which malignant B-cells protect themselves from 
phagocytosis by activated macrophages. However, CD47/SIRPα interaction not only regulates phagocytosis 
but also has a role in modulating T-cell function by enhancing antigen presentation, effectively making the 
CD47/SIRPα axis an immune checkpoint for the innate immune system. 
We hypothesize that CD14+SIRPαhigh TAMs are highly functional, able to phagocytose malignant cells, present 
tumor antigens and activate the immune system but are inhibited by CD47. In contrast, CD14-SIRPαlow/- TAMs 
are immature, fail to phagocytose malignant cells and suppress immune function. To improve the outcome of 
lymphoma patients, the phagocytosis and T-cell activation by both CD14+SIRPαhigh and CD14-SIRPαlow/- TAMs 
needs to be augmented. We therefore propose to determine the phagocytic function and immune activation of 
both CD14+SIRPαhigh and CD14-SIRPαlow/- TAMs, and determine whether blocking CD47/SIRPα signaling 
clinically using SIRPα-Fc can enhance the tumor-directed phagocytic function of both populations of TAMs. We 
anticipate that results from this project will lead not only to a comprehensive understanding of the subtypes of 
TAMs in lymphoma, but an innovative therapy that harnesses the power of both the innate and adaptive 
immune systems.

## Key facts

- **NIH application ID:** 9988171
- **Project number:** 5P50CA097274-19
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** STEPHEN M ANSELL
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $251,021
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988171

## Citation

> US National Institutes of Health, RePORTER application 9988171, Project 1: Activating Phagocytic Macrophages in non-Hodgkin Lymphoma (5P50CA097274-19). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9988171. Licensed CC0.

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