1.
Creative Biolabs
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info@creative-biolabs.com
Macrophages
as Targets in Cancer
Immunotherapy

2.
Introduction into Macrophages
Macrophage Polarization
Tumor-Associated Macrophages
Functions of Macrophages in Cancers
Strategies for Targeting Macrophages for Tumor
Immunotherapy
Selected Clinical Trials of Agents Targeting TAMs
Services at Creative Biolabs
• Promotion of angiogenesis
• Induction of invasiveness and metastasis
• Regulation of the tumor microenvironment
• Induction of therapeutic resistance
• Suppression of macrophage recruitment
• Reduction of macrophage survival
• Inhibition of tumor-promoting functions
• Removal of the macrophage blockade
• Induction of repolarization
• Modification of effector cells
Table of Contents
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Macrophage is a type of white blood cell that
surrounds and kills microorganisms, removes dead
cells, and stimulates the action of other immune system
cells.
Possible Origins of Macrophage:
(1) Yolk sac that mainly resides in tissues such as the
liver, spleen, lung, brain, pancreas, and kidney;
(2) Bone marrow;
(3) Langerhans cells from the fetal liver;
(4) Extramedullary hematopoiesis, especially in the
spleen.
Development and Differentiation of Macrophages
Zhaojun Duan & Yunping Luo, Signal Transduction and Targeted Therapy, 2021
Introduction into Macrophages
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4.
• M1 and M2 are classifications historically used to define
macrophages activated in vitro as pro-inflammatory (M1) or
anti-inflammatory (M2), respectively.
• However, in vivo macrophages are highly specialized,
transcriptomically dynamic, and extremely heterogeneous with
regard to their phenotypes and functions, which are
continuously shaped by their tissue microenvironment.
• Therefore, the M1 or M2 classification is too simplistic to
explain the true nature of in vivo macrophages, although these
terms are still often used to indicate whether the macrophages
in question are more pro-inflammatory or anti-inflammatory. Zhaojun Duan & Yunping Luo, Signal Transduction and Targeted
Therapy, 2021
M1–M2 Macrophage Polarization
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5.
David G. DeNardo & Brian Ruffell, Nature Reviews Immunology, 2019
Polarization State of Macrophages
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6.
• The tumor microenvironment (TME) provides an essential ecological niche
for cancer initiation and progression.
• Inflammatory cells and mediators are key universal components of the
TME, and tumor-associated macrophages (TAMs) have served as a
paradigm for the connection between inflammation and cancer.
• It has long been held that TAMs originate from bone marrow (BM)-derived
monocytic precursors, which replenish the tumor compartment.
• Functions of macrophages in cancers:
(1) Promotion of angiogenesis
(2) Induction of invasiveness and metastasis
(3) Regulation of the tumor microenvironment
(4) Induction of therapeutic resistance
Tumor-Associated Macrophages
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7.
Zhaojun Duan & Yunping Luo, Signal Transduction and
Targeted Therapy, 2021
• Macrophages are deeply involved in vasculogenesis and
lymphogenesis.
• In addition, TAMs can enhance tumor hypoxia and glycolysis,
two important causes of angiogenesis.
• Macrophages also stimulate vascular endothelial cells to produce
VEGF.
• Depletion of TAMs inhibits angiogenesis.
Functions of Macrophages in Cancers: Promotion of
Angiogenesis
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8.
Zhaojun Duan & Yunping Luo, Signal Transduction and Targeted Therapy, 2021
• Macrophages dissolve the extracellular matrix to pave the
path for tumor cell escape.
• TAMs upregulate cytokines, such as IL-1ra, to promote
metastasis by enhancing tumor cell stemness.
• Secretion of TGF-β and growth factors promotes
epithelial–mesenchymal transition and invasiveness of
tumor cells.
• Exosomes released from M2 macrophages are
responsible for cancer metastasis by transferring certain
miRNAs into cancer cells.
• Macrophages can also assist in tumor survival and
colonization at premetastatic lesions.
Functions of Macrophages in Cancers: Induction of Invasiveness
and Metastasis
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9.
Zhaojun Duan & Yunping Luo, Signal Transduction and Targeted Therapy, 2021
Tumor-associated macrophages support a suppressive
tumor microenvironment in three ways:
(1) by consuming the metabolites,
(2) by producing the cytokines and chemokines,
(3) by expressing inhibitory molecules.
Functions of Macrophages in Cancers: Regulation of the Tumor
Microenvironment
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10.
Zhaojun Duan & Yunping Luo, Signal Transduction and
Targeted Therapy, 2021
Chemotherapy
• Macrophages can activate STAT3 in tumor cells, which
enhances the proliferation and survival of malignant cells under
treatment with several chemotherapeutics.
• TAMs contribute to chemoresistance by inducing prosurvival
and antiapoptotic signals in cancer cells, as well as their
protumoral polarization.
Radiotherapy
• Irradiation promotes the accumulation and M2 polarization of
macrophages. Inhibition of differentiation of M2 macrophages
showed enhanced responses to radiotherapy in breast cancer.
Functions of Macrophages in Cancers: Induction of Therapeutic
Resistance
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11.
(1) Suppression of macrophage recruitment
Inhibitors or antibodies against CCL2/5, CCR2/5,
CSF1, CSF1R, VEGF, VEGFR, ITGA4, CXCR4,
C5a, NRP1, ANG2, et al.
(2) Reduction of macrophage survival
CSF1 inhibitors, trabectedin, bisphosphonates,
immunotoxins against scavenger receptor-A or FRβ.
Strategies for Targeting Macrophages for Tumor Immunotherapy
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12.
(3) Inhibition of tumor-promoting functions
Inhibiting activation: TIM-3 blocking antibody.
Inhibiting angiogenesis: anti-VEGF/anti-
VEGFR, tyrosine kinase inhibitors.
Targeting immunosuppression: aspirin,
inhibitors or antibodies of IDO, heme
oxygenase, arginase, TGF-β, IL-10, PD-L1,
PD-L2, B7-H4, VISTA, B7-1, and B7-2.
(4) Removal of the macrophage blockade
Antibodies against CD47, SIRPα, MUC1,
EGFR, et al.
Strategies for Targeting Macrophages for
Tumor Immunotherapy
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13.
(5) Induction of repolarization
Inducing M1 polarization: IFNγ, CD40 agonists,
inhibitors of PI3Kγ, mTOR, DICER, TLR agonists of
TLR4, 7, 8 or 9, methionine sulfoximine, HDAC
inhibitors, MARCO antibody.
Inhibiting M2 polarization: CSF1R inhibitors, corosolic
acid, omeprazole, Gpr132 inhibitors, MEK/STAT3
inhibitors, fasting-mimicking diets, antibodies of IL-4,
IL-4Ra, IL-13.
(6) Modification of effector cells
CAR-macrophage targeting CD19, HER2
mesothelin, et al.
Strategies for Targeting Macrophages for
Tumor Immunotherapy
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14.
Category
Compound
(Sponsor)
Clinical Phase
(Status)
Tumor Type
Combination
Partners
NCT Identifier
Chemokine inhibitors
CCR5 antagonist
(Pfizer)
Phase I (completed) CRC Pembrolizumab NCT03274804
CSF1R inhibitors BLZ945 (Novartis) Phase I/II (ongoing) Solid tumors PDR001 (anti-PD1) NCT02829723
Anti-CSF1R antibodies
LY3022855 (IMC-CS4;
Eli Lilly)
Phase I/II (ongoing) Melanoma MEK/BRAF inhibitors NCT03101254
Anti-CD47/SIRPα
antibodies
Hu5F9-G4 (Stanford
University)
Phase I/II (completed) Solid tumors Cetuximab NCT02953782
Complement inhibitors
Hiltonol (Oncovir,
Inc.)
Phase II (completed) Solid tumors
Autologous dendritic
cells
NCT01734564
Agonist anti-CD40
antibodies
RO7009789 (Roche) Phase I (completed) Pancreatic cancer
Nab-paclitaxel and
gemcitabine
NCT02588443
Alberto Mantovani et al., Nature Reviews Drug Discovery, 2022
Selected Clinical Trials of Agents Targeting Tumor-Associated
Macrophages
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15.
Services at Creative Biolabs
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First-in-class
Macrophage Therapeutic
Development Service
Macrophage Isolation
and Culture
Macrophage
Polarization Assay
Macrophage Phenotype
Identification
Macrophage
Characterization
Macrophage
Reprogramming
Macrophage Marker
Development
Macrophage-Targeted
Drug Delivery System
Development
Macrophage
Engineering for Drug
Delivery
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