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Published on: December 7, 2019
TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation
Andrea C Pichler1, Nadège Carrié2, Marine Cuisinier3
1Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université Toulouse III-Paul Sabatier (UPS), Toulouse, France; Cell Signaling and Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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.
Insights
CD137 (4-1BB) signaling drives the expansion and differentiation of exhausted T cells (Tex), impacting cancer immune surveillance. Targeting CD137 influences anti-PD1 therapy efficacy in preclinical models.
Area of Science:
- Immunology
- Cancer Biology
- T cell Biology
Background:
- CD137 (4-1BB) is a promising target for cancer immunotherapy.
- The precise role of CD137 in cancer immune surveillance and T cell exhaustion remains unclear.
Purpose of the Study:
- To elucidate the cellular programs regulated by CD137.
- To investigate CD137's role in T cell exhaustion and its implications for cancer immunotherapy.
Main Methods:
- Utilized T cell-specific deletion models and agonist antibodies targeting CD137.
- Investigated T cell-intrinsic signaling pathways, including NF-κB and Tox.
- Employed preclinical mouse models to assess tumor growth and anti-PD1 therapy efficacy.
Main Results:
- CD137 signaling modulates the infiltration of exhausted CD8+ T cells (Tex) expressing PD1, Lag-3, and Tim-3.
- T cell-intrinsic CD137 signaling promotes Tex precursor proliferation and terminal differentiation via NF-κB and Tox.
- Prophylactic CD137 agonism enhanced tumor growth, but subsequent CD137 stimulation improved anti-PD1 efficacy.
Conclusions:
- CD137 is a critical regulator of exhausted T cell expansion and differentiation.
- Understanding CD137's role in T cell exhaustion has significant implications for cancer and infectious disease treatments.
- CD137 targeting holds broad therapeutic potential for enhancing cancer immunotherapy.
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