Releasing the brake: targeting Cbl-b to enhance lymphocyte effector functions

Clin Dev Immunol. 2012;2012:692639. doi: 10.1155/2012/692639. Epub 2012 Apr 10.

Abstract

The E3 ubiquitin ligase Cbl-b is an established nonredundant negative regulator of T-cell activation. Cbl-b fine-tunes the activation threshold of T cells and uncouples T cells from their vital need of a costimulatory signal to mount a productive immune response. Accordingly, mice deficient in cblb are prone to autoimmunity and reject tumors. The latter has been described to be mediated via CD8(+) T cells, which are hyperactive and more abundant in shrinking tumors of cblb-deficient animals. This might at least also in part be mediated by resistance of cblb-deficient T cells to negative cues exerted by tumor-associated immuno-suppressive factors, such as TGF-β and regulatory T cells (Treg). Experiments using cblb-deficient T cells either alone or in combination with vaccines validate the therapeutic concept of enhancing the efficacy of adoptively transferred lymphocytes to treat malignant tumors. This paper summarizes the current knowledge about the negative regulatory role of Cbl-b in T-cell activation and its potential therapeutic implications for cancer immunotherapy.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / therapeutic use
  • Humans
  • Immunotherapy / methods*
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Knockout
  • Neoplasms* / immunology
  • Neoplasms* / prevention & control
  • Neoplasms* / therapy
  • Proto-Oncogene Proteins c-cbl / deficiency
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / immunology*
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Transforming Growth Factor beta / immunology

Substances

  • Cancer Vaccines
  • Transforming Growth Factor beta
  • Proto-Oncogene Proteins c-cbl