CD137 共刺激拮抗 TGF-β 对 NK 细胞抗肿瘤功能的抑制

Enhancing natural killer (NK) cell-based cancer immunotherapy by overcoming immunosuppression is an area of intensive research.

Here, we have demonstrated that the anti-CD137 agonist urelumab can overcome TGF -mediated inhibition of human NK-cell proliferation and antitumor function. Transcriptomic, immunophenotypic, and functional analyses showed that CD137 costimulation modified the transcriptional program induced by TGF on human NK cells by rescuing their proliferation in response to IL2, preserving their expression of activating receptors (NKG2D) and effector molecules (granzyme B, IFN ) while allowing the acquisition of tumor-homing/retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGF 1 and CD137 agonist recovered CCL5 and IFN secretion and showed enhanced direct and antibody-dependent cytotoxicity upon restimulation with cancer cells.

Trastuzumab treatment of fresh breast carcinoma-derived multicellular cultures induced CD137 expression on tumor-infiltrating CD16 + NK cells, enabling the action of urelumab, which fostered tumor-infiltrating NK cells and recapitulated the enhancement of CCL5 and IFN production.

Bioinformatic analysis pointed to IFNG as the driver of the association between NK cells and clinical response to trastuzumab in patients with HER2-positive primary breast cancer, highlighting the translational relevance of the CD137 costimulatory axis for enhancing IFN production.

Our data reveals CD137 as a targetable checkpoint for overturning TGF constraints on NK-cell antitumor responses.