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Macrophages impair PD-1 immunotherapy in melanoma

Macrophages appear to be a driving factor behind resistance to PD-1 checkpoint blockade immunotherapy to melanoma, researchers report in Science Translational Medicine (Apr. 11, 2018; 10(436):eaan3311).

“The existence of immune cells that either execute or suppress cytotoxic immune responses is essential for limiting the potentially deleterious effects of an uncontrolled immune response, a condition that may lead to auto-immunity or organ damage,” said study author Professor Michele De Palma, PhD, in a press release. “The problem is that tumours hijack these regulatory mechanisms to their own benefit, so that they can grow largely unchecked by the immune system.”

Dr. De Palma is an assistant professor of cancer biology and research lab leader at École polytechnique fédérale de Lausanne in Lausanne, Switzerland.

The authors note that CD8 T cells—cytotoxic T lymphocytes—recognize and destroy melanoma cells, and that some forms of immunotherapy stimulate the CD8 T cells to attack the tumour more vigorously.

Investigators analyzed samples taken from the tumours of melanoma patient tumours and found that CD8 T cells, while working against the melanoma, also stimulate the release of a protein—CSF1—which attracts macrophages to the area. When they arrive, the macrophages impair the activity of the CD8 T cells.

The authors suggest their findings support the testing of agents that disrupt macrophages in conjunction with PD-1 immunotherapy in patients who have melanoma tumours that contain large numbers of both CD8 T cells and macrophages.

“As opposed to targeted therapies that hit specific oncogenes responsible for the growth of the tumour, immunotherapies largely lack biomarkers that can predict whether a patient will respond or not to the treatment,” said Dr. De Palma.

“Our study suggests that assessing the abundance of macrophages and the contextual presence of CD8 T-cells—for example by measuring genes that are specifically expressed by these cells—may serve to stratify patients who are amenable to more effective immunotherapy combinations,” said study author Dr. Daniel Speiser, a professor in the department of oncology, Université de Lausanne, in Lausanne, Switzerland.

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