| First Author | Pichler AC | Year | 2023 |
| Journal | Immunity | Volume | 56 |
| Issue | 7 | Pages | 1631-1648.e10 |
| PubMed ID | 37392737 | Mgi Jnum | J:338436 |
| Mgi Id | MGI:7511351 | Doi | 10.1016/j.immuni.2023.06.007 |
| Citation | Pichler AC, et al. (2023) TCR-independent CD137 (4-1BB) signaling promotes CD8(+)-exhausted T cell proliferation and terminal differentiation. Immunity 56(7):1631-1648.e10 |
| abstractText | 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-kappaB 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. |
