The macrophage checkpoint CD47: SIRPa for recognition of 'self' cells: From clinical trials of blocking antibodies to mechanobiological fundamentals

Abstract

Immunotherapies against some solid tumour types have recently shown unprecedented, durable cures in the clinic, and the most successful thus far involves blocking inhibitory receptor 'checkpoints' on T cells. A similar approach with macrophages is emerging by blocking the ubiquitously expressed 'marker of self' CD47 from binding the inhibitory receptor SIRPa on macrophages. Here, we first summarize available information on the safety and efficacy of CD47 blockade, which raises some safety concerns with the clearance of 'self' cells but also suggests some success against haematological (liquid) and solid cancers. Checkpoint blockade generally benefits from parallel activation of the immune cell, which can occur for macrophages in multiple ways, such as by combination with a second, tumour-opsonizing antibody and perhaps also via rigidity sensing. Cyto-skeletal forces in phagocytosis and inhibitory 'self'-signalling are thus reviewed together with macrophage mechanosensing, which extends to regulating levels of SIRPa and the nuclear protein lamin A, which affects phenotype and cell trafficking. Considerations of such physical factors in cancer and the immune system can inform the design of new immunotherapies and help to refine existing therapies to improve safety and efficacy. This article is part of a discussion meeting issue 'Forces in cancer: interdisciplinary approaches in tumour mechanobiology'.