Complement inhibitor factor H expressed by breast cancer cells differentiates CD14⁺ human monocytes into immunosuppressive macrophages

ABSTRACT

Macrophages are a major immune cell type in the tumor microenvironment, where they display a tumor-supporting phenotype. Factor H (FH) is a complement inhibitor that also plays a role in several cellular functions. To date, the phenotype of monocytes stimulated with FH has been unexplored. We discovered that FH is a survival factor for CD14⁺ primary human monocytes, promoting their differentiation into macrophages in serum-free medium. This activity was localized to the C-terminal domains of FH and it was inhibited in plasma, indicating that the phenomenon may be most relevant in tissues. FH-induced macrophages display characteristics of immunosuppressive cells including expression of CD163 and CD206, release of the anti-inflammatory cytokine IL-10 and changes in metabolism. Furthermore, FH-induced macrophages express low levels of HLA-DR but high levels of co-inhibitory molecule programmed death-ligand 1 (PD-L1), and accordingly, a reduced capacity for T-cell activation. Finally, we show that FH is expressed by human breast cancer cells and that this correlates with the presence of immunosuppressive macrophages, breast cancer recurrence and severity of the disease. We propose that the expression of FH by tumor cells and the promotion of an immunosuppressive cancer microenvironment by this protein should be taken into account when considering the effectiveness of immunotherapies against breast cancer.

KEYWORDS:

• Breast cancer
• macrophages
• factor H

Acknowledgments

We thank Dr Peter Storm for the bioinformatic analyses, Dr Ben King, Lund University, for discussions and language revision of the manuscript and Mrs Ekström-Holka for help with immunochemical stainings.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This study was supported by the Swedish Research Council [2016-01142 and 2018-02392], Cancerfonden, Foundations of Österlund, King Gustav V´s 80th Anniversary, Knut and Alice Wallenberg, and grants for clinical research (ALF and the Skåne University Hospital).