ABSTRACT

Cancer immunotherapy based on Immune checkpoint blockade (ICB) is a promising strategy to treat patients with advanced highly aggressive therapy-resistant tumors. Unfortunately, the clinical reality is that only a small number of patients benefit from the remarkable clinical remissions achieved by ICB. Experimental and clinical evidence claimed that durable clinical benefit observed using ICB depends on the immune status of tumors, notably the presence of cytotoxic effector immune cells. In our paper, we revealed that genetically targeting the autophagy-related protein PIK3C3/VPS34 in melanoma and colorectal tumor cells, or treating tumor-bearing mice with selective inhibitors of the PIK3C3/VPS34 kinase activity, reprograms cold immune desert tumors into hot, inflamed immune infiltrated tumors. Such reprograming results from the establishment of a proinflammatory signature characterized by the release of CCL5 and CXCL10 in the tumor microenvironment, and the subsequent recruitment of natural killer (NK) and CD8⁺ T cells into the tumor bed. Furthermore, we reported that combining pharmacological inhibitors of PIK3C3/VPS34 improves the therapeutic benefit of anti-PD-1/PD-L1 immunotherapy. Our results provided the proof-of-concept to set-up innovative clinical trials for cold ICB-unresponsive tumors by combining PIK3C3/VPS34 inhibitors with anti-PDCD1/PD-1 and anti-CD274/PD-L1.

摘要

基于免疫检查点阻断 (ICB) 的癌症免疫疗法是治疗晚期高度侵袭性耐药肿瘤患者的一种有前途的策略。不幸的是，临床现实是只有少数患者受益于 ICB 取得的显着临床缓解。实验和临床证据声称，使用 ICB 观察到的持久临床益处取决于肿瘤的免疫状态，特别是细胞毒性效应免疫细胞的存在。在我们的论文中，我们揭示了基因靶向黑色素瘤和结直肠肿瘤细胞中的自噬相关蛋白 PIK3C3/VPS34，或用 PIK3C3/VPS34 激酶活性的选择性抑制剂治疗荷瘤小鼠，将冷免疫沙漠肿瘤重新编程为热、发炎的肿瘤。免疫浸润性肿瘤。⁺ T 细胞进入肿瘤床。此外，我们报道了联合使用 PIK3C3/VPS34 的药理学抑制剂提高了抗 PD-1/PD-L1 免疫疗法的治疗效果。我们的研究结果为通过将 PIK3C3/VPS34 抑制剂与抗 PDCD1/PD-1 和抗 CD274/PD-L1 相结合来建立针对冷 ICB 无反应肿瘤的创新临床试验提供了概念验证。