CBL0137 与 NKG2A 阻断：一种针对 Myc 过表达三阴性乳腺癌的新型免疫肿瘤联合疗法

The MYC proto-oncogene is upregulated in >60% of triple-negative breast cancers (TNBCs), it can directly promote tumor cell proliferation, and its overexpression negatively regulates anti-tumor immune responses. For all these reasons, MYC has long been considered as a compelling therapeutic target.

However, pharmacological inhibition of MYC function has proven difficult due to a lack of a drug-binding pocket.

Here, we demonstrate that the potent abrogation of MYC gene transcription by CBL0137 induces immunogenic cell death and reduces proliferation in MYC-high but not in MYC-low TNBC in vitro. CBL0137 also significantly inhibited the in vivo growth of primary tumors in a human MYC-high TNBC xenograft model (MDA-MB-231).

Moreover, CBL0137 inhibited the tumor growth of highly aggressive mouse 4T1. 2 syngeneic TNBC model in immunocompetent mice by inhibiting the MYC pathway and inducing Type I interferon responses. Immune profiling of CBL0137-treated mice revealed significantly enhanced tumor-specific immune responses and increased proportions of tumor infiltrating effector CD8 + T cells, CD4 + T cells, and NK cells. CBL0137-induced immune activation also resulted in increased exhaustion of immune effector cells.

In particular, NKG2A up-regulation on activated effector cells and of its ligand Qa-1 b on tumors in vivo was identified as a possible immune evasive mechanism. Indeed, NKG2A blockade synergized with CBL0137 significantly inhibiting the in vivo growth of 4T1. 2 tumors. Collectively, our findings provide the rationale supporting the exploitation of CBL0137-induced anti-tumor immunity in combination with NKG2A blockade to improve the treatment of TNBC expressing high levels of MYC.