PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer
PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer
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DOI：
10.1073/pnas.1822001116
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发表时间：
2019-05-14
影响因子：
11.1
通讯作者：
Nishikawa, Hiroyoshi
中科院分区：
文献类型：
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作者：
Kamada, Takahiro;Togashi, Yosuke;Nishikawa, Hiroyoshi
PD-1阻断是一种对多种癌症有效的肿瘤免疫疗法。然而，在一小部分接受治疗的患者中，它会导致癌症快速进展，称为超进行性疾病（HPD）。通过观察大约10%的抗pd -1单克隆抗体（mAb）治疗的晚期胃癌（GC）患者的HPD，我们探讨了抗pd -1 mAb如何导致这些患者的HPD以及如何治疗和预防HPD。在大多数GC患者中，肿瘤浸润性FoxP3（高）CD45RA(-)CD4(+) T细胞[效应Treg （eTreg）细胞]表达PD-1的水平与肿瘤浸润性CD4（+）或CD8（+）效应/记忆T细胞相当，且远高于循环性eTreg细胞。比较抗pd -1单抗治疗前后的GC组织样本显示，治疗显著增加了HPD患者的肿瘤浸润性增殖（Ki67(+)） eTreg细胞，而非HPD患者则减少了这种细胞。功能上，循环和肿瘤浸润的PD-1(+) eTreg细胞被高度激活，CTLA-4的表达高于PD-1-eTreg细胞。PD-1阻断显著增强体外Treg细胞抑制活性。同样，在小鼠中，基因消融或抗体介导的阻断Treg细胞中的PD-1可增加其增殖并抑制抗肿瘤免疫反应。综上所述，PD-1阻断可能促进高抑制性PD-1(+) eTreg细胞在HPDs中的增殖，从而抑制抗肿瘤免疫。因此，肿瘤中活跃增殖的PD-1(+) eTreg细胞的存在是HPD的可靠标志。在PD-1阻断癌症免疫治疗中，肿瘤组织中eTreg细胞的缺失可以有效地治疗和预防HPD。
PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in similar to 10% of anti-PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti-PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3(high)CD45RA(-)CD4(+) T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4(+) or CD8(+) effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti-PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67(+)) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1(+) eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1-eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1(+) eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1(+) eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.