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.

基于免疫检查点封锁（ICB）的癌症免疫疗法是一种有前途的策略，可用于治疗具有高度高度侵袭性的抗药性晚期肿瘤的患者。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，尤其是细胞毒性效应免疫细胞的存在。在我们的论文中，我们揭示了遗传靶向黑素瘤和结直肠肿瘤细胞中自噬相关蛋白PIK3C3 / VPS34，或用PIK3C3 / VPS34激酶活性的选择性抑制剂治疗荷瘤小鼠，将冷的免疫沙漠肿瘤重编程为炎热，发炎的免疫浸润性肿瘤。⁺ T细胞进入肿瘤床。此外，我们报道了将PIK3C3 / VPS34的药物抑制剂组合使用可提高抗PD-1 / PD-L1免疫疗法的治疗效果。我们的结果为PIK3C3 / VPS34抑制剂与抗PDCD1 / PD-1和抗CD274 / PD-L1组合使用，为建立针对ICB无反应的寒冷肿瘤的创新性临床试验提供了概念验证。