Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer.
Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer.
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DOI：
10.1158/0008-5472.can-14-1913
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发表时间：
2014-12-15
期刊：
影响因子：
11.2
通讯作者：
Sikora AG
中科院分区：
文献类型：
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作者：
Parikh F;Duluc D;Imai N;Clark A;Misiukiewicz K;Bonomi M;Gupta V;Patsias A;Parides M;Demicco EG;Zhang DY;Kim-Schulze S;Kao J;Gnjatic S;Oh S;Posner MR;Sikora AG
虽然HPV相关口咽癌(HPVOPC)中的病毒抗原是有吸引力的免疫治疗靶点，但现有的标准护理疗法对HPV免疫应答的影响尚不清楚。我们连续采集了接受同期放化疗(CRT)的III-IV期OPC患者的血液样本，包括诱导化疗和非诱导化疗。用流式细胞仪检测外周血中的免疫细胞，包括CD4+和CD8+T细胞、调节性T细胞(Treg)和髓系抑制细胞(MDSC)。检测抗原特异性T细胞对HPV16E6和E7多肽池的反应。PD-1信号在治疗相关免疫抑制中的作用是通过在封闭抗体存在的情况下进行HPV特异性T细胞检测来确定的。治疗前18例患者中有13例出现HPV特异性T细胞反应，而13例患者中有10例在CRT后3个月内消失。CRT使循环T细胞减少，MDSC明显升高。在CRT后，CD4+T细胞上PD-1的表达增加了近2.5倍，体外培养的PD-1封闭抗体增强了8/18个受试者的HPV特异性T细胞反应。CRT通过不利地改变效应者：抑制者免疫细胞比率和上调CD4+T细胞上PD-1的表达来抑制HPVOPC患者的循环免疫反应。这些数据有力地支持了PD-1阻断剂与标准护理CRT联合用于HPVOPC的测试。
While viral antigens in HPV-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from stage III–IV OPC patients undergoing concomitant chemoradiotherapy (CRT) with or without induction chemotherapy. Circulating immunocytes including CD4+ and CD8+ T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T cell assays in the presence of blocking antibody. While HPV-specific T cell responses were present in 13/18 patients prior to treatment, 10/13 patients lost these responses within 3 months after CRT. CRT decreased circulating T cells and markedly elevated MDSC. PD-1 expression on CD4+ T cells increased by nearly 2.5-fold after CRT, and ex-vivo culture with PD-1 blocking antibody enhanced HPV-specific T cell responses in 8/18 samples tested. CRT suppresses circulating immune responses in HPVOPC patients by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4+ T cells. These data strongly support testing of PD-1-blocking agents in combination with standard-of-care CRT for HPVOPC.