CD137 costimulation counteracts TGFβ inhibition of NK cell anti-tumor function and promotes the acquisition of tissue-resident Th9-like properties [4 treatments]

Enhancing NK cell-based cancer immunotherapy by overcoming immunosuppression is an unmet goal. Here, we demonstrate the ability of the anti-CD137 agonist urelumab for overcoming TGF-β-mediated inhibition of human NK-cell proliferation and sustained anti-tumor function. Transcriptomic, immunophenotypic and functional analyses evidenced that CD137 costimulation modified the transcriptional program induced by TGF-β on activated NK cells by limiting SMAD4-dependent inhibition of pro-proliferative (CD25, cMyc), activating (NKG2D, CD16) and effector (Granzyme B, IFNγ) molecules while maintaining SMAD4-independent acquisition of tumor-retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGF-β1 and CD137 agonist showed preserved antibody-dependent cytotoxicity against cancer cells, recovered CCL5 and IFNγ secretion and gained the capacity for producing IL-9 upon restimulation. Treatment of breast tumor-derived multicellular cultures with trastuzumab and urelumab recapitulated CD137 induction and fostered tumor-infiltrating CD16+ NK cell persistence. Our data reveals CD137 as a targetable checkpoint for overturning TGF-β constrains on NK cell anti-tumor responses. A total of 12 samples were analyzed: 4 different treatments (KD1, KT, KTU and NT) in purified NK cells from 3 volunteer donors.