Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence.

化疗通常会产生瘤内衰老癌细胞，这些细胞会强烈改变肿瘤微环境，有利于免疫抑制和肿瘤生长。通过无偏见的蛋白质组学筛选，我们发现免疫检查点抑制剂程序性细胞死亡 1 配体 2 (PD-L2) 在不同类型的癌细胞中诱导衰老后高度上调。PD-L2 并不是细胞衰老所必需的，但它对于衰老细胞逃避免疫系统并在瘤内持续存在至关重要。事实上，化疗后，PD-L2 缺陷的衰老癌细胞被迅速消除，并且肿瘤不会产生衰老相关趋化因子 CXCL1 和 CXCL2。因此，PD-L2 缺陷的胰腺肿瘤无法募集骨髓源性抑制细胞，并且在化疗后由 CD8 T 细胞驱动消退。最后，抗体介导的 PD-L2 阻断与化疗产生强烈协同作用，导致小鼠乳腺肿瘤缓解。化疗与抗 PD-L2 的组合提供了一种利用治疗引起的衰老所产生的脆弱性的治疗策略。