New tools to prevent cancer growth and spread: a 'Clever' approach

Br J Cancer. 2020 Aug;123(4):501-509. doi: 10.1038/s41416-020-0953-0. Epub 2020 Jun 29.

Abstract

Clever-1 (also known as Stabilin-1 and FEEL-1) is a scavenger receptor expressed on lymphatic endothelial cells, sinusoidal endothelial cells and immunosuppressive monocytes and macrophages. Its role in cancer growth and spread first became evident in Stab1-/- knockout mice, which have smaller primary tumours and metastases. Subsequent studies in mice and humans have shown that immunotherapeutic blockade of Clever-1 can activate T-cell responses, and that this response is mainly mediated by a phenotypic change in macrophages and monocytes from immunosuppressive to pro-inflammatory following Clever-1 inhibition. Analyses of human cancer cohorts have revealed marked associations between the number of Clever-1-positive macrophages and patient outcome. As hardly any reports to date have addressed the role of Clever-1 in immunotherapy resistance and T-cell dysfunction, we performed data mining using several published cancer cohorts, and observed a remarkable correlation between Clever-1 positivity and resistance to immune checkpoint therapies. This result provides impetus and potential for the ongoing clinical trial targeting Clever-1 in solid tumours, which has so far shown a shift towards immune activation when a particular epitope of Clever-1 is blocked.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Disease Progression
  • Drug Resistance, Neoplasm*
  • Humans
  • Immunotherapy
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / immunology
  • Receptors, Lymphocyte Homing / genetics*
  • Receptors, Lymphocyte Homing / metabolism
  • T-Lymphocytes / metabolism

Substances

  • Cell Adhesion Molecules, Neuronal
  • Receptors, Lymphocyte Homing
  • STAB1 protein, human
  • Stab1 protein, mouse