PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity.
PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity.
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DOI：
10.1084/jem.20160801
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发表时间：
2017-04-03
期刊：
影响因子：
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通讯作者：
Sharpe AH
中科院分区：
文献类型：
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作者：
Juneja VR;McGuire KA;Manguso RT;LaFleur MW;Collins N;Haining WN;Freeman GJ;Sharpe AH
肿瘤和宿主来源的PD-L1都可以在免疫抑制中发挥关键作用；肿瘤免疫原性的差异似乎是它们相对贡献的基础。Juneja等人。表明在免疫原性MC38肿瘤中，肿瘤细胞上的PD-L1主要通过抑制CD8 T细胞的细胞毒作用来抑制肿瘤免疫。目前尚不清楚肿瘤细胞上的PD-L1是否足以逃避肿瘤免疫，或者只是与炎症的肿瘤微环境有关。我们使用了三种对PD-1拮抗剂敏感的小鼠肿瘤模型来评估PD-L1对肿瘤细胞和非肿瘤细胞的意义。非肿瘤细胞上的PD-L1在抑制B16黑色素瘤和基因工程黑色素瘤的抗肿瘤免疫中起关键作用。相反，MC38结肠腺癌细胞上的PD-L1足以抑制抗肿瘤免疫，因为高免疫原性MC38肿瘤细胞上PD-L1的缺失可以实现有效的抗肿瘤免疫。MC38来源的PD-L1能有效抑制CD8+T细胞的细胞毒作用。野生型MC38细胞在体内的竞争优于PD-L1缺失的MC38细胞，表明肿瘤PD-L1具有选择性优势。因此，肿瘤来源和宿主来源的PD-L1都可以在免疫抑制中发挥关键作用。肿瘤免疫原性的差异似乎是它们相对重要性的基础。我们的发现确立了降低细胞毒性是肿瘤PD-L1抑制抗肿瘤免疫的关键机制，并证明了肿瘤PD-L1不仅仅是抗肿瘤免疫抑制的标志。
Both tumor- and host-derived PD-L1 can play critical roles in immunosuppression; differences in tumor immunogenicity appear to underlie their relative contributions. Juneja et al. show that in immunogenic MC38 tumors, PD-L1 on tumor cells dominates in suppressing tumor immunity by inhibiting CD8 T cell cytotoxicity. It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8+ T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1–deleted MC38 cells in vivo, demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Differences in tumor immunogenicity appear to underlie their relative importance. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.