CBL0137 and NKG2A blockade: a novel immuno-oncology combination therapy for Myc-overexpressing triple-negative breast cancers
- Author(s)
- Raninga, PV; Zeng, B; Moi, D; Trethowan, E; Saletta, F; Venkat, P; Mayoh, C; D'Souza, RCJ; Day, BW; Shai-Hee, T; Vittorio, O; Mazzieri, R; Dolcetti, R; Khanna, KK;
- Journal Title
- Oncogene
- Publication Type
- Online publication before print
- Abstract
- 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.
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1038/s41388-024-03259-y
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Creation Date: 2025-01-21 06:45:08
Last Modified: 2025-01-21 06:46:48