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.

很少有三阴性乳腺癌 (TNBC) 患者受益于免疫检查点抑制剂，完全和持久的缓解非常罕见。致癌基因可以调节肿瘤免疫浸润，但是致癌基因是否决定了对免疫治疗的反应减弱以及这些影响是否可逆仍然知之甚少。在这里，我们报告了 MYC 表达升高的 TNBC 对免疫检查点抑制剂治疗有抵抗力。使用小鼠模型和患者数据，我们表明 MYC 信号与低肿瘤细胞 PD-L1、低整体免疫细胞浸润和低肿瘤细胞 MHC-I 表达相关。恢复肿瘤中的干扰素信号可增加 MHC-I 表达。通过将 TLR9 激动剂和抗 OX40 的激动性抗体与抗 PD-L1 相结合，小鼠经历了肿瘤消退并免受新的 TNBC 肿瘤生长的影响。我们的研究结果表明，MYC 依赖性免疫逃避是可逆的和可药物化的，并且当战略性地靶向时，可以改善接受免疫检查点抑制剂治疗的患者的结果。