The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

Cell Res. 2020 Apr;30(4):285-299. doi: 10.1038/s41422-020-0277-x. Epub 2020 Jan 23.


Co-inhibitory receptors are important regulators of T-cell function that define the balance between tolerance and autoimmunity. The immune regulatory function of co-inhibitory receptors, including CTLA-4, PD-1, TIM-3, TIGIT, and LAG-3, was first discovered in the setting of autoimmune disease models, in which their blockade or deficiency resulted in induction or exacerbation of the disease. Later on, co-inhibitory receptors on lymphocytes have also been found to influence outcomes in tumor and chronic viral infection settings. These receptors suppress T-cell function in the tumor microenvironment (TME), thereby making the T cells dysfunctional. Based on this observation, blockade of co-inhibitory receptors (also known as checkpoint molecules) has emerged as a successful treatment option for a number of human cancers. However, severe autoimmune-like side effects limit the use of therapeutics that block individual or combinations of co-inhibitory receptors for cancer treatment. In this review we provide an overview of the role of co-inhibitory receptors in autoimmunity and anti-tumor immunity. We then discuss current approaches and future directions to leverage our knowledge of co-inhibitory receptors to target them in tumor immunity without inducing autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Autoimmunity*
  • Humans
  • Immune Checkpoint Proteins / physiology*
  • Immunotherapy
  • Neoplasms / metabolism*
  • Neoplasms / therapy
  • T-Lymphocyte Subsets* / immunology
  • T-Lymphocyte Subsets* / pathology
  • Tumor Microenvironment*


  • Immune Checkpoint Proteins