The CD47-SIRP alpha immune checkpoint

The cytotoxic activity of myeloid cells is regulated by a balance of signals that are transmitted through inhibitory and activating receptors. The Cluster of Differentiation 47 (CD47) protein, expressed on both healthy and cancer cells, plays a pivotal role in this balance by delivering a "don't eat me signal'' upon binding to the Signal-regulatory protein alpha (SIRP alpha) receptor on myeloid cells. Here, we review the current understanding of the role of the CD47-SIRP alpha axis in physiological tissue homeostasis and as a promising therapeutic target in, among others, oncology, fibrotic diseases, atherosclerosis, and stem cell therapies. We discuss gaps in understanding and highlight where additional insight will be beneficial to allow optimal exploitation of this myeloid cell checkpoint as a target in human disease.Dermatology-oncolog

Depletion of Trp53 and Cdkn2a does not promote self-renewal in the mammary gland but amplifies proliferation induced by TNF-α

Dermatology-oncolog

A mouse model that is immunologically tolerant to reporter and modifier proteins

Reporter proteins have become an indispensable tool in biomedical research. However, exogenous introduction of these reporters into mice poses a risk of rejection by the immune system. Here, we describe the generation, validation and application of a multiple reporter protein tolerant 'Tol' mouse model that constitutively expresses an assembly of shuffled reporter proteins from a single open reading frame. We demonstrate that expression of the Tol transgene results in the deletion of CD8(+) T cells specific for a model epitope, and substantially improves engraftment of reporter-gene transduced T cells. The Tol strain provides a valuable mouse model for cell transfer and viral-mediated gene transfer studies, and serves as a methodological example for the generation of poly-tolerant mouse strains. Bresser and Dijkgraaf et al. develop the 'Tol' strain, a genetically modified mouse model that expresses a range of shuffled reporter and modifier proteins from a single open reading frame. This strain is immunologically tolerant to these reporter and modifier proteins, providing a valuable model system for cell transfer studies and virus-mediated gene transfer studies.Dermatology-oncolog

Genetic Screening for Novel Regulators of Immune Checkpoint Molecules

Inhibitory and stimulatory immune checkpoint molecules play important roles in regulating immune responses. An increasing number of these immune regulators are currently being evaluated as targets in putative anti-cancer therapies. Recently, sophisticated genetic screens have been performed to increase our understanding of immune checkpoint pathways and their immunomodulatory regulators. Here, we summarize novel insights obtained by these screens and discuss new directions to advance possible strategies to treat malignancies.Experimental cancer immunology and therap

Inhibition of the Epigenetic Reader BRD4 Reduces SIRP alpha-Mediated Phagocytosis and Melanoma Invasion

BRD4 acts as an epigenetic reader to regulate gene transcription. It represents a valid therapeutic target in cancer, and several selective and potent small molecule inhibitors have been discovered. A study by Le et al. (2020) published in Journal of Investigative Dermatology (2020) demonstrates that BRD4 inhibition reduces the invasive behavior of melanoma cells associated with matrix metalloproteinase-2 downregulation and increases phagocytosis by myeloid cells through SIRP alpha downregulation.Experimental cancer immunology and therap

CD47/SIRP alpha axis: bridging innate and adaptive immunity

Myeloid immune cells are frequently present in the tumor environment, and although they can positively contribute to tumor control they often negatively impact anticancer immune responses. One way of inhibiting the positive contributions of myeloid cells is by signaling through the cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRP alpha) axis. The SIRP alpha receptor is expressed on myeloid cells and is an inhibitory immune receptor that, upon binding to CD47 protein, delivers a 'don't eat me' signal. As CD47 is often overexpressed on cancer cells, treatments targeting CD47/SIRP alpha have been under active investigation and are currently being tested in clinical settings. Interestingly, the CD47/SIRP alpha axis is also involved in T cell-mediated antitumor responses. In this perspective we provide an overview of recent studies showing how therapeutic blockade of the CD47/SIRP alpha axis improves the adaptive immune response. Furthermore, we discuss the interconnection between the myeloid CD47/SIRP alpha axis and adaptive T cell responses as well as the potential therapeutic role of the CD47/SIRP alpha axis in tumors with acquired resistance to the classic immunotherapy through major histocompatibility complex downregulation. Altogether this review provides a profound insight for the optimal exploitation of CD47/SIRP alpha immune checkpoint therapy.Experimental cancer immunology and therap