Targeting Tumor-Associated Macrophages

Introduction

Tumor-associated macrophages (TAMs), which are commonly identified by expression of CD163, CD204, or CD206, are prominent immune cells that orchestrate various stromal responses in the tumor microenvironment (TME). In extreme cases, TAM could represent up to 50% of the tumor mass. TAMs produce cytokines or mitogens to affect the initiation and progression of cancer. The higher numbers of TAMs might be connected with worse clinical outcomes in many cancers. TAMs can also dispose at the tumor margin, where they can interact with cytotoxic T lymphocytes (CTLs), thus inhibiting their infiltration towards tumor cells.

Macrophages are a heterogeneous population of cells in TME, that can be approximately induced into two contrasting groups: M1- and M2-like macrophages. M1-like macrophages show an anti-tumor function (Fig.1). M2-like macrophages, regarded as 'friends' by cancer cells, have been generally thought to promote tumor initiation, progression, angiogenesis, and metastasis.

Fig.1 Anti-tumor and pro-tumor functions of TAMs. (Anfray, 2020)

Mechanisms of TAM-Mediated Immunosuppression

TAM-mediated immunosuppression in the TME is essentially mediated by several concurrent mechanisms:

• TAMs help the tumor establish a pro-inflammatory TME and secrete manifold growth factors and cytokines to help oncogenesis, inhibit effector T cells function directly, promote angiogenesis, as well as factors recruiting regulatory T cells (Treg).
• TAMs subvert local immune surveillance by expression of ligands for lymphocyte suppressor factors PD-1 and CTLA-4, i.e., PDL-1 and CD80. In addition, the depletion of L-arginine and the production of immunosuppressive metabolites such as indolamine-2,3-dioxygenase (IDO) limit the proliferation of cytotoxic T cells as well as expanding Treg.
• TAMs are beneficial to produce several proteolytic enzymes and motor-related proteins to support the invasion and metastasis of tumors.
• TAMs encode multiple gene products and produce cytokines, vascular endothelial growth factor (VEGF), etc. to promote angiogenesis.

Macrophages‑targeted Immunotherapies

In many solid tumor types, TAMs are important components of the TME, and TAM infiltration is strongly associated with poor clinical outcomes for patients. Based on these findings, targeting TAMs is an attractive strategy for solid tumor therapeutic intervention. The therapeutic strategies include: 1) clearing macrophages and inhibiting the activation of TAMs, 2) limiting monocyte recruitment, 3) reprogramming M2‑like TAMs into the M1‑like phenotype by anti-CD47 antibodies, CD40 agonists, PI3Kγ inhibitors, 4) targeting TAMs such as inhibition of PD-L1 antibody to promote macrophage phagocytic activity, 5) targeting TAMs complements anti-angiogenic therapy.

What Can We Offer

With the help of extensive experience and scientific teams in CAR-T therapy, Creative Biolabs is confident to offer One-Stop CAR-Macrophage Therapy Development Services. We also have developed a macrophage development platform to provide macrophage reprogramming service, Macrophage Polarization Assay, etc. For more detailed information, please feel free to contact us.

References

1. Anfray, Clément, et al. "Current strategies to target tumor-associated-macrophages to improve anti-tumor immune responses." Cells 9.1 (2019): 46. Distributed under Open Access license CC BY 4.0, without modification.