It has become appreciated in recent years that the immune system plays a key role in the pathogenesis of many diseases in which it was previously discounted. In particular, cancer immunology has been a rising area of research within immunology. It was named the breakthrough of the year by Science magazine in 2013, and since then, new developments in both basic research and in the clinic have propelled the field even further. While clinical advances have made their way into the news, exciting research happening in model systems, both in vitro and in vivo, has been less popularized but equally exciting. Macrophages, in particular, are becoming newly appreciated in the field of cancer immunology. One particularly interesting topic is the diversity of roles of macrophages within the tumor microenvironment (TME).
Many reports highlight a pro-tumorigenic role for tumor-associated macrophages (TAM). This is based on the ability of macrophages to suppress immune responses in a variety of tissues and pathologic settings, including cancer, via the secretion of IL-10 and TGFβ, by promoting the recruitment or differentiation of T regulatory cells (Tregs), and by inducing expression of CTLA4 and PD-1 on T cells. However, it has also been postulated that due to their expression of FcRs, which bind antibodies, macrophages may play a role in antibody-mediated cell death. Antibodies (such as those targeting CTLA4, PD-1, and HER2/neu) are a common form of cancer immunotherapy.
A recent publication by Lehmann et al. in Science Immunology showed that despite their ability to promote tumor progression, macrophages are also required for the efficacy of antibody-mediated immunotherapy in a murine model of melanoma. This study sheds light on the complex and diverse roles that macrophages may play in TME and the anti-tumor immune response. In particular, it builds upon previous work implicating myeloid cells in mediating therapeutic effects following treatment with antibody-based therapies by determining that the site of the tumor defines which FcγR+ macrophage subset contributes to this effect.
The authors assayed B16F10 melanoma developing in the skin versus lung and determined that the macrophage subset required for therapeutic efficacy following treatment with TA99 (anti-TRP1 antibody) differed between sites. In skin tumors, the efficacy of TA99 treatment was mediated by FcγR+ blood monocytes recruited to the site of the tumor via the CCL2-CCR2 axis. This paradigm was paralleled in subcutaneous EL4 (lymphoma) tumors. Therapeutic efficacy of TA99 against melanoma growing in the lung was independent of CCR2, and was instead dependent upon tissue-resident macrophages expressing FcγR. Conversely, the presence of blood-derived macrophages appeared to promote tumor progression in the lung. These results suggest that a finer characterization of macrophage phenotypes may be necessary to selectively promote or inhibit specific subsets to shift the intratumoral immune response following therapeutic intervention.
It also begs for a stronger understanding of the variation between the particular FcγR that a therapeutic antibody requires to mediate its effect. While the study by Lehmann focused on the activating receptors FcγRI and IV, used by TA99, Wilson et. al previously showed that therapeutic antibodies targeting DR4, DR5, and CD40 may at least partly depend on inhibitory Fc receptors, such as FcγRIIb and FcγRIII. In combination with understanding of the role of each FcγR-expressing cell type within the TME, an ability to manipulate the FcγR targeted by an antibody might help in the design of future therapies by tailoring the antibody to target specific subsets of immune cells, such as macrophages, or a particular FcγR polymorphism.
As with other immune cell types, including T cells (the current target of many immunotherapies), one size clearly does not fit all when it comes to macrophages in the TME. Instead, understanding which macrophage subsets are present in tumors throughout the body and their role in the anti-tumor immune response will be crucial for developing interventions that enhance or inhibit the functions of specific macrophage populations.
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Aliyah is a PhD candidate at the University of Pittsburgh, where she studies cancer immunology. She is also an advocate for science communication. You can find her on Twitter @desabsurdites and on her blog at http://isntthatgrad.wordpress.com/.