The impact of antibody isotype on patient monocyte and macrophage functions and activation states to manipulate anti-tumour responses in melanoma

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The rates of cutaneous malignant melanoma, the deadliest form of skin cancer, are continuing to increase in the UK despite new therapies available for patients. Melanomas develop when UV radiation from sunlight causes mutations in the DNA of melanocytes, or pigment cells, in the skin, allowing them to multiply, grow, invade local structures and spread to other parts of the body. One reason why melanoma can be so deadly is because cancer cells can create inflammation within the tumour and recruit immune cells which they can control. Macrophages are one such cell type which is found in melanoma tumours. Macrophages normally help our immune system to clear infections and then to restore order in tissues following the destruction caused by invading pathogen. However, we have shown that macrophages can be brought in tumours and these tumour-associated macrophages can be manipulated to help tumours to grow, spread, and together with cancer cells, create an environment which makes it harder for the immune system to fight the cancer. Tumour-associated macrophages are large immune cells found in cancer lesions that have been studied extensively in other cancers but less so in melanoma. The studies which have been undertaken so far have shown that if there are more macrophages in the melanoma tumour, patients with these tumours are more likely to have more advanced disease and have a worse outcome. It is likely that signals from the melanoma cells can change the function of macrophages, causing them to aid melanoma growth and reduce the immune response to the cancer, although the exact mechanisms of these are unknown. In addition to this, monocytes in the blood, which can become macrophages once they arrive in tissues, may be different in patients with melanoma when compared to healthy people, and may display a reduced ability to create an effective immune response against the cancer. This study aims to explore the difference in monocytes in healthy volunteers and patients with melanoma, revealing how monocytes are recruited to the melanoma tumour and how they can be controlled by signals from the melanoma and from the immune system. We ultimately wish to understand how these cells change their function when they encounter monoclonal antibodies. Monoclonal antibodies which recognise targets on cancer cells are part of a growing field of using the body's own immune system to treat cancer. Monoclonal antibodies bind to both targets on cancer cells and receptors on immune cells, triggering responses in these immune cells which ultimately lead to a stronger immune response and killing of the cancer. The binding of antibodies on macrophage receptors may influence the macrophages to become better at killing cancer cells, making treatment more effective. A better understanding of these important cells in the context of melanoma and how they can be awakened by antibodies may uncover not only potential new targets for treatments, but also give us a better understanding of the disease process, and how monoclonal antibodies can be used successfully improve treatment for patients with melanoma.