Cblb-deficient T cells are less susceptible to PD-L1-mediated inhibition

Oncotarget. 2017 Jun 27;8(26):41841-41853. doi: 10.18632/oncotarget.18360.

Abstract

Modulation of the immune system for the treatment of primary and metastatic tumors has been a goal of cancer research for many years. The E3 ubiquitin ligase Cbl-b has been established as an intracellular checkpoint that limits T cell activation, critically contributing to the maintenance of self-tolerance. Furthermore, it has been shown that Cblb deficiency enhances T cell effector functions towards tumors. Blockade of the immune checkpoints CTLA-4 and PD-1/PD-L1 has recently emerged as a promising strategy in the development of effective cancer immune therapies. Therefore, we explored the concept of targeting different checkpoints concomitantly. Interestingly, we observed that CTLA-4 but not PD-L1 based immunotherapy selectively enhanced the anti-tumor phenotype of Cblb-deficient mice. In agreement with the in vivo results, in vitro experiments showed that Cblb-/- T cells were less susceptible to PD-L1-mediated suppression of T cell proliferation and IFNγ secretion. Taken together, our findings reveal a so far unappreciated function of Cbl-b in the regulation of PD-1 signaling in murine T cells.

Keywords: Cbl-b; T cells; cancer immunotherapy; immune checkpoints.

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency*
  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / metabolism*
  • CTLA-4 Antigen / antagonists & inhibitors
  • Cell Proliferation / drug effects
  • Disease Susceptibility*
  • Female
  • Immunomodulation* / genetics
  • Interferon-gamma / metabolism
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Knockout
  • Neoplasms / drug therapy
  • Neoplasms / etiology
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Proto-Oncogene Proteins c-cbl / deficiency*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Tumor Burden / drug effects

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CTLA-4 Antigen
  • Cblb protein, mouse
  • Interferon-gamma
  • Proto-Oncogene Proteins c-cbl