Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1

Abstract

Classically activated M1 macrophages and alternatively activated M2 macrophages are two polarized subsets of macrophages at the extreme ends of a constructed continuum. In the field of cancer research, M2 macrophage reprogramming is defined as the repolarization of pro-tumoral M2 to anti-tumoral M1 macrophages. It is known that colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R) and CSF2/CSF2R signaling play important roles in macrophage polarization. Targeting CSF1/CSF1R for M2 macrophage reprogramming has been widely performed in clinical trials for cancer therapy. Other targets for M2 macrophage reprogramming include Toll-like receptor 7 (TLR7), TLR8, TLR9, CD40, histone deacetylase (HDAC), and PI3Kγ. Although macrophages are involved in innate and adaptive immune responses, M1 macrophages are less effective at phagocytosis and antigen presenting, which are required properties for the activation of T cells and eradication of cancer cells. Similar to T and dendritic cells, the “functionally exhausted” status might be attributed to the high expression of programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1). PD-L1 is expressed on both M1 and M2 macrophages. Macrophage reprogramming from M2 to M1 might increase the expression of PD-L1, which can be transcriptionally activated by STAT3. Macrophage reprogramming or PD-L1/PD-1 blockade alone is less effective in the treatment of most cancers. Since PD-L1/PD-1 blockade could make up for the defect in macrophage reprogramming, the combination of macrophage reprogramming and PD-L1/PD-1 blockade might be a novel treatment strategy for cancer therapy.

CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells

“…Its impact on CSF1R inhibition is unclear in relapsing FLT3-ITD AML, and its clinical activity is predominantly related to its ability to inhibit FLT3 [ 91 ]. CSF1R inhibition alone may not be sufficient to overcome resistance mechanisms in vivo [ 92 , 93 ], but it may represent a general approach to target the microenvironment of AML cells and may be promising when used in combination with inhibitors of the immune checkpoints, angiogenesis, or with the adoptive T-cell transfer, which are undergoing clinical investigations [ 94 ].…”

Differential Cytokine-Induced Responses of Polarized Microglia

“…On comparing PD-L1 expression between M0- and M2-polarized microglial cells, we observed a significant decrease in the percentage of M2-polarized cells expressing PD-L1 after treatment with both pro- (LPS, IFN-γ and IL-1β) and anti- (IL-4 and IL-10) inflammatory stimulants as compared to M0-microglial cells ( Figure 5 ). It has been shown in the case of macrophages that PD-L1 is expressed on both M1 and M2 cells, and there is an increased expression when the macrophages are polarized from M2 to M1 [ 44 ].…”

Double Strike Approach for Tumor Attack: Engineering T Cells Using a CD40L:CD28 Chimeric Co-Stimulatory Switch Protein for Enhanced Tumor Targeting in Adoptive Cell Therapy

“…Recent studies highlight the importance of IL-1ß secretion by intratumoral DCs for the maintenance of CD8 effector T cells in the TME ( 83 ) and IL-10 for re-programming exhausted CD8 T cells ( 84 ). Upregulation of PD-L1 on DCs was seen after contact with CD40L:CD28 CSP-expressing T cells suggesting that reprogramming of tumor-conditioned myeloid cells ( 85 ) together with checkpoint inhibition could be the next step forward to improve cancer immunotherapy ( 86 , 87 ). The here reported activation of a pro-inflammatory secretome in TME-conditioned ercDCs is an encouraging sign that CD40L:CD28 CSPs might be able to promote myeloid cell repolarization in the TME.…”