Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer

Abstract

Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects are reversible remains poorly understood. Here, we report that TNBCs with elevated MYC expression are resistant to immune checkpoint inhibitor therapy. Using mouse models and patient data, we show that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, mice experience tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and when strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.

MYC and therapy resistance in cancer: risks and opportunities

“…Likewise, suppressing MYC via epigenetic therapy reverted immune evasion in a mouse lung cancer model [ 118 ]. Finally, a retrospective analysis of several clinical studies suggested that elevated MYC expression might be associated with resistance to immune checkpoint inhibitor therapy in metastatic urothelial carcinoma and possibly other cancer types, including TNBC [ 119 ]. While the significance of these associations remains to be confirmed, the same study reported that MYC‐induced anti‐PD‐L1 resistance could be overcome with a combinatorial immuno‐therapeutic regimen in a preclinical model of TNBC.…”

Dissecting the contributions of tumor heterogeneity on metastasis at single-cell resolution

“…( E ) Pathway enrichment of DEGs shared between highly metastatic tumors. ( F ) Scatterplot shows the correlation of MYC (42) and immune regulation signature expression colored by tumor model. Pearson correlation coefficient is shown.…”

“…MYC signaling was among the top 5 enriched pathways in highly metastatic primary tumors (Supplementary Figure S3E). MYC signaling can lead to evasion from immune surveillance by the suppression of interferon signaling and antigen-presentation pathways including the down-regulation of B2M and MHC-I (41, 42). This anti-correlation could explain the observed upregulation of immune regulatory pathways in poorly metastatic compared to highly metastatic primary tumors that showed elevated MYC signaling (Supplementary Figure S3F).…”

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

“…MYC can act as a transcriptional activator of PD-L1 [ 81 ]. It was shown to drive immune evasion by decreasing immune cell infiltration and HLA class I expression [ 82 ]. The downregulation of PTEN promoted the proliferation of NSCLCs by increasing the expression of PD-L1 [ 83 ].…”