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化疗的效果受到肿瘤内表达PD-L2的衰老细胞的限制

原文发布日期：2024-01-24

英文摘要：

摘要翻译：

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化疗的效果受到肿瘤内表达PD-L2的衰老细胞的限制

The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2

原文发布日期：2024-01-24

英文摘要：

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.

摘要翻译：

化疗通常会产生肿瘤内 senior癌细胞，这些细胞会显著改变肿瘤微环境，促进免疫抑制和肿瘤生长。我们通过一种无偏 proteomics 筛查发现，在多种癌症细胞中，免疫检查点抑制剂程序性死亡 1 受体结合蛋白 2 (PD-L2) 在诱导 senescence后高度上调表达。然而，PD-L2 不是导致 cell 原发性的必要因素，但它对于 senior cells 避免免疫系统识别并长期存在于肿瘤内部至关重要。事实上，化疗后缺乏 PD-L2 的 senior 癌细胞被快速清除，肿瘤不会产生与 senescence相关的促迁移到断言 CXCL1 和 CXCL2 蛋白。因此，缺乏 PD-L2 的胰腺肿瘤无法吸引髓系间充质细胞抑制器并受到 CD8 T 细胞化疗后介导的消退驱动。最后，通过抗体靶向阻断 PD-L2 强烈协同化疗导致小鼠乳腺癌消退。将化疗与 anti-PD-L2 抗体结合治疗为一种利用诱导 senescence 出现的易 targets 的治疗策略。