ED31 enhanced the antitumor efficacy of anti-CTLA-4 in C57BL/6J mice bearing B16F10 or Pan02 tumors.
The combination of ED31 with anti-CTLA-4 significantly increased immune cell infiltration in the .
Mature conventional dendritic cell recruitment was notably enhanced by the addition of ED31 to anti-CTLA-4 treatment.
A shift to M1-pattern chemokines produced by macrophages was observed when ED31 was combined with anti-CTLA-4.
Depleting macrophages eliminated the increased immune cell infiltration and chemokine production, as well as the antitumor efficacy of the therapy.
Targeting MARCO may improve the effectiveness of anti-CTLA-4 therapy through the reprogramming of macrophages rather than their depletion.
Simplified
BACKGROUND: Strategies to improve the therapeutic efficacy of cancer immunotherapy with immune checkpoint inhibitors include targeting additional immunosuppressive compartments in the (TME). Inhibitory macrophages (Mφ) can be one of the most abundant immune cells in the TME associated with poor prognosis. However, to date, selective Mφ depletion strategies as a cancer immunotherapy have not been successful in clinical trials. Macrophage Receptor with Collagenous Structure (MARCO) is one of a family of class-A scavenger receptors expressed by Mφ in the TME and is one of the most upregulated transcripts in dendritic cells (DC) following their ex vivo uptake of dead tumor cells. The clinical significance of MARCO expression in the TME is not fully understood.
METHODS: The therapeutic potential of targeting MARCO by an anti-murine MARCO (ED31, clone ED31) monoclonal antibody, which inhibits ligand-binding to MARCO, was explored in combination with anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) or anti-programmed cell death protein-1 (anti-PD-1) in C57BL/6J mice bearing B16F10 or Pan02 tumors. The mechanism by which ED31 impacts the TME was investigated by flow cytometry in the different treatment arms. The contribution of Mφ was assessed by both in vivo depletion and in vitro functional assays. Chemokine production was measured by a bead-based multiplex assay.
RESULTS: ED31 enhanced antitumor efficacy of anti-CTLA-4, but not of anti-PD-1. Analysis of the TME revealed that adding ED31 to anti-CTLA-4 substantially increased immune cell infiltration, including mature conventional DC recruitment, that was due to a switch to M1-pattern chemokines by Mφ. Mφ depletion completely abrogated both the increase in immune cell infiltration and chemokine production, and abolished the antitumor efficacy of the combination therapy.
CONCLUSIONS: Targeting MARCO as an additional checkpoint in the TME can offer a strategy to improve the antitumor efficacy of anti-CTLA-4 through a mechanism involving Mφ reprogramming rather than their depletion.
Key numbers
10 cells/cm
Increase in immune cell density
Total immune cells (CD45) density in the after treatment with ED31 and anti-CTLA-4.
n=35 (αCTLA-4+ED31) vs. n=15 (αCTLA-4 alone)
Survival comparison
Survival outcomes in mice treated with ED31 and anti-CTLA-4 versus anti-CTLA-4 alone.
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Competing interests: JJM has ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, Ankyra Therapeutics, and AffyImmune Therapeutics, and is a paid consultant/paid scientific and/or clinical advisory board member for Turnstone Biologics, Vault Pharma, Ankyra Therapeutics, AffyImmune Therapeutics, UbiVac, Vycellix, and Aleta Biotherapeutics, as well as a Board of Directors member of CG Oncology.
