Innate immune myeloid cells including monocytes and macrophages are classically activated to clear pathogens and promote immunity, but these same cells are reprogramed within tumor microenvironments to become tumor-associated macrophages (TAMs) where they suppress anti-tumor immunity and promote tumor growth. Studies investigating biological mechanisms behind anti-tumor ?M1-like? classical maturation versus tumor-promoting ?M2-like? alternative maturation have therapeutic potential. Our lab and others have shown that paired Ig-like receptor B (PIR-B), a receptor expressed on myeloid lineages in mice, and suppresses immune activation. We further showed that PIR-B maintains the M2-like phenotype of tumor infiltrating monocytes. Mice deficient in PIR-B have reduced tumor burdens and an infiltrating monocyte profile that resembled M1-like classical activation. The leukocyte immunoglobulin-like receptor subfamily B (LILRB) represents the human ortholog of mouse PIR-B. Like PIR-B, LILRB expression is restricted to myeloid cell populations. Our group generated a panel of antibodies against LILRB family members and screened for functional activity in human monocyte-derived macrophage cell-based assays. Consistent with our findings in mouse, we observed that LILRB antibody antagonists promote classical M1-like activation. Concordantly, macrophages downregulate M2-associated markers and enhance TNF? while suppressing IL-10 secretion, a profile consistent with M1 classical maturation. We hypothesize that LILRB is an important homeostatic regulator that suppresses human monocyte classical activation.
Two specific aims will be pursued: 1) To elucidate how LILRB signaling suppresses classical activation in human macrophages. 2) To determine the effect of LILRB blockade on monocyte/macrophage maturation using in vivo patient-derived xenograft (PDX) models. Studies of the cellular and molecular mechanisms of action utilized by LILRB antagonists coupled with in vivo PDX models are critical for understanding LILRB function in myelopoeisis. Successful completion of these studies will result in a better understanding of how findings from mouse PIRB translate to the human LILRB. Furthermore, our PDX models will indicate if LILRB blockade alters the tumor microenvironment and enhances anti-tumor immunity. These findings may lead to the discovery of novel and specific targets on TAMs that can be used to combat the immune suppression associated with advanced malignancies. The ablation of immune suppression should significantly augment the efficacy of existing immune-based therapies for treatment of advanced metastatic cancer.

Public Health Relevance

Tumor-Associated macrophages (TAM) are responsible for supporting an environment that promotes cancer progression and immune escape. Our project goal is to understand the mechanism of how LILRB receptors control TAM function. Results from this study will be used to better design TAM-targeted therapies that improve cancer immunotherapeutic drug efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI122715-01A1
Application #
9192101
Study Section
Special Emphasis Panel (ZRG1-F07-T (21))
Program Officer
Gondre-Lewis, Timothy A
Project Start
2016-06-15
Project End
2017-06-14
Budget Start
2016-06-15
Budget End
2017-06-14
Support Year
1
Fiscal Year
2016
Total Cost
$58,002
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029