Targeting the Complement Cascade: A Novel Therapeutic Strategy for Metastatic Melanoma (2016–2018)
Preliminary studies in our laboratory have provided compelling evidence that a key element of the innate immune system, the complement anaphylatoxin C3a, promotes tumour growth. We have evidence of complement activation in human melanoma and lung cancer. Moreover we have shown in mouse models of melanoma that tumour growth and metastasis are markedly reduced in mice lacking the C3a receptor (C3aR), and that primary tumour growth can be arrested by administration of a C3aR antagonist. We also have evidence that C3aR deficiency results in mobilisation of neutrophils, with increased tumour infiltrating neutrophils, leading to alterations in T cell populations. Our demonstration that C3aR is expressed by melanoma cells suggests that C3a may also affect tumour cells directly. Hypothesis: Complement component C3a is a critical regulator of melanoma growth and metastasis, exerting its effects indirectly via regulation of immune cell populations within the tumour environment, and directly via effects on tumour cell growth. Aims: 1. To validate C3aR as a therapeutic target for metastatic melanoma using mouse models; 2. To explore how C3a-C3aR signalling influences immune cell populations in metastatic tissue; 3. To determine whether C3a-C3aR signalling has direct effects on tumour cell growth and metastasis; 4. To examine the potential of C3aR as a therapeutic target for other metastatic cancers. Significance: This research investigates a novel mechanism by which the innate immune system can be directed towards an anti-tumour response, and will determine the feasibility of the C3aR as a therapeutic target for metastatic melanoma. The availability of C3aR targeting drugs, with more in the developmental pipeline, will facilitate progression of this research to pre-clinical and clinical trials.