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Review
. 2022 Oct 3;11(1):2127284.
doi: 10.1080/2162402X.2022.2127284. eCollection 2022.

Influencing tumor-associated macrophages in malignant melanoma with monoclonal antibodies

Rebecca Adams  1 , Gabriel Osborn  1 , Bipashna Mukhia  1 , Roman Laddach  1   2 , Zena Willsmore  1 , Alicia Chenoweth  1   3 , Jenny L C Geh  1   4 , Alastair D MacKenzie Ross  4 , Ciaran Healy  4 , Linda Barber  5 , Sophia Tsoka  2 , Victoria Sanz-Moreno  6 , Katie E Lacy  1 , Sophia N Karagiannis  1   3
Affiliations
Review

Influencing tumor-associated macrophages in malignant melanoma with monoclonal antibodies

Rebecca Adams et al. Oncoimmunology. .

Abstract

The application of monoclonal antibodies (mAbs) for the treatment of melanoma has significantly improved the clinical management of this malignancy over the last decade. Currently approved mAbs for melanoma enhance T cell effector immune responses by blocking immune checkpoint molecules PD-L1/PD-1 and CTLA-4. However, more than half of patients do not benefit from treatment. Targeting the prominent myeloid compartment within the tumor microenvironment, and in particular the ever-abundant tumor-associated macrophages (TAMs), may be a promising strategy to complement existing therapies and enhance treatment success. TAMs are a highly diverse and plastic subset of cells whose pro-tumor properties can support melanoma growth, angiogenesis and invasion. Understanding of their diversity, plasticity and multifaceted roles in cancer forms the basis for new promising TAM-centered treatment strategies. There are multiple mechanisms by which macrophages can be targeted with antibodies in a therapeutic setting, including by depletion, inhibition of specific pro-tumor properties, differential polarization to pro-inflammatory states and enhancement of antitumor immune functions. Here, we discuss TAMs in melanoma, their interactions with checkpoint inhibitor antibodies and emerging mAbs targeting different aspects of TAM biology and their potential to be translated to the clinic.

Keywords: Fc receptors; checkpoint inhibitors; immunotherapy; macrophages; melanoma; monoclonal antibodies; polarization; tumor microenvironment.

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Conflict of interest statement

S.N.K. is the founder and shareholder of Epsilogen Ltd. and declares patents on antibody technologies.

Figures

Figure 1.
Figure 1.
Defining macrophage subsets in the melanoma tumor microenvironment includes (1) using the classical/alternatively activated spectrum model (far left); (2) using differentially expressed genes to define subsets from single cell data (top); (3) understanding how the TME can promote subsets with specific functions (right); and (4) understanding how macrophage origin can determine phenotype and function (bottom left).
Figure 2.
Figure 2.
TAMs can promote melanoma growth and progression by creating an immunosuppressive immune environment by recruiting and maintaining immunosuppressive cells, such as Tregs, M2-like TAMs and MDSCs and reducing effector cells activation; promoting angiogenesis directly by secreting VEGF and MIF and indirectly through TNF-α and IL-1 α promoting angiogenesis by melanoma cells; enabling invasion by secreting metalloproteinases; and enabling metastasis by promoting the secretion of factors which increase phenotype switching (TGF-β), increase motility (IL-8), and increase invasion (IL-6). Created with BioRender.com.
Figure 3.
Figure 3.
Current techniques to therapeutically target TAMs include (a) involvement of TAMs in current immune checkpoint inhibition; (b) reducing recruitment of macrophages to the TME, e.g. by blocking CCR2/CCL2 and CSF-1/CSFR1 pathways; (c) inhibiting pro-tumor functions of TAMS; (d) promoting antitumor functions of TAMS; (e) depleting specific pro-tumor subsets of TAMs; (f) repolarizing TAMs through the engagement of their FcRs, triggering downstream activation, increased secretion of pro-inflammatory cytokines and enhanced cancer cell death. Created with BioRender.com.
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