Clinical evaluation of macrophages in cancer: role in treatment, modulation and challenges

Abstract

The focus of immunotherapeutics has been placed firmly on anti-tumour T cell responses. Significant progress has been made in the treatment of both local and systemic malignancies, but low response rates and rising toxicities are limiting this approach. Advancements in the understanding of tumour immunology are opening up a new range of therapeutic targets, including immunosuppressive factors in the tumour microenvironment. Macrophages are a heterogeneous group of cells that have roles in innate and adaptive immunity and tissue repair, but become co-opted by tumours to support tumour growth, survival, metastasis and immunosuppression. Macrophages also support tumour resistance to conventional therapy. In preclinical models, interference with macrophage migration, macrophage depletion and macrophage re-education have all been shown to reduce tumour growth and support anti-tumour immune responses. Here we discuss the role of macrophages in prognosis and sensitivity to therapy, while examining the significant progress which has been made in modulating the behaviour of these cells in cancer patients.

Keywords: Cancer; Immunology; Immunotherapy; Macrophage.

Fig. 1

Magnitude of immune potential versus tumour generated immunosuppression. Diagrammatic hypothesis representing immunosuppression over time during cancer progression graphed with immune potential. Immune potential is the ability of the immune system to mount an effective adaptive immune response

Fig. 2

Synopsis of M1:M2 macrophage dichotomy. CD11b monocytes (MO) can mature with a heterogeneity of phenotypes which together represent a spectrum with M1 and M2 macrophages representing the two extremes of that spectrum. In vitro, IFNγ, LPS and TNFα drive M1 polarization whereas IL-4, IL-10 and IL-13 drive M2 polarization. M1 macrophages express CD68, CD11b, CD38. CD16/32, MHC II and CD80/86, their primary function is dependent on the expression and function of inducible nitric oxide synthase (iNOS) which results in the extracellular accumulation of nitric oxide (NO) and citrulline which, along with other cytokines, can drive cytotoxic anti-tumour T_h1 responses. M2 macrophages express CD68, CD11b, CD163, CD206, Galectin 3 and Egr2, their primary function is dependent on the expression and function of arginase which results in the extracellular depletion of arginine and the accumulation of ornithine and urea which are key to wound repair mechanisms but can also promote immune suppression and tumour progression

Fig. 3

Synopsis of pro- and anti- tumoural effects exerted by macrophages. Key enzymes and cytokines produced by M1 and M2 macrophages that have the effect of driving or inhibiting cancer progression. M1 cells can drive inflammation and cytotoxic T_h1 responses while M2 cells can produce factors such as vascular endothelial growth factor (VEGF) and Prostaglandin E2 (PGE2), and are involved in the depletion of activated T cells, recruitment of regulatory T cells, tissue remodelling, angiogenesis and tumour progression