The Untold Story of Granzymes in Oncoimmunology: Novel Opportunities with Old Acquaintances

Trends Cancer. 2017 Jun;3(6):407-422. doi: 10.1016/j.trecan.2017.04.001. Epub 2017 Jun 9.

Abstract

For more than 20 years perforin and granzymes (GZMs) have been recognized as key cell death executors of cytotoxic T (Tc) and natural killer (NK) cells during cancer immunosurveillance. In immune surveillance, perforin and GZMB, the most potent cytotoxic molecules, act mainly as antitumoral and anti-infectious factors. However, when expressed by immune regulatory cells they may contribute to immune evasion of specific cancer types. By contrast, the other major granzyme, GZMA, seems not to play a major role in Tc/NK cell-mediated cytotoxicity, but acts as a proinflammatory cytokine that might contribute to cancer development. Members of the GZM family also regulate other biological processes unrelated to cell death, such as angiogenesis, vascular integrity, extracellular matrix remodeling, and barrier function, all of which contribute to cancer initiation and progression. Thus, a new paradigm is emerging in the field of oncoimmunology. Can GZMs act as protumoral factors under some circumstances? We review the diverse roles of GZMs in cancer progression, and new therapeutic opportunities emerging from targeting these protumoral roles.

Keywords: cancer progression; extracellular matrix; granzymes; inflammation.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers
  • Disease Progression
  • Disease Susceptibility
  • Extracellular Matrix / immunology
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / pathology
  • Granzymes / antagonists & inhibitors
  • Granzymes / genetics
  • Granzymes / metabolism*
  • Humans
  • Immune System / cytology
  • Immune System / immunology
  • Immune System / metabolism
  • Immunity
  • Immunologic Surveillance
  • Immunomodulation
  • Lymphocyte Activation / immunology
  • Molecular Targeted Therapy
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neoplasms / therapy
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology

Substances

  • Biomarkers
  • Granzymes

Grant support