TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation

Immunity. 2023 Jul 11;56(7):1631-1648.e10. doi: 10.1016/j.immuni.2023.06.007. Epub 2023 Jun 30.

Abstract

CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8+-exhausted T (Tex) cells expressing PD1, Lag-3, and Tim-3 inhibitory receptors. T cell-intrinsic, TCR-independent CD137 signaling stimulated the proliferation and the terminal differentiation of Tex precursor cells through a mechanism involving the RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. While Tex cell accumulation induced by prophylactic CD137 agonists favored tumor growth, anti-PD1 efficacy was improved with subsequent CD137 stimulation in pre-clinical mouse models. Better understanding of T cell exhaustion has crucial implications for the treatment of cancer and infectious diseases. Our results identify CD137 as a critical regulator of Tex cell expansion and differentiation that holds potential for broad therapeutic applications.

Keywords: CD137 (TNFRSF9, 4-1BB); CD8(+) T lymphocytes; NF-κB signaling; T cell exhaustion; activation receptor; immune checkpoint blockade; immunotherapy; tumor immune escape.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes*
  • Cell Differentiation
  • Cell Proliferation
  • Mice
  • Neoplasms*
  • Receptors, Antigen, T-Cell
  • Tumor Necrosis Factor Receptor Superfamily, Member 9

Substances

  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Receptors, Antigen, T-Cell