Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer
Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer
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DOI：
10.1136/jitc-2020-000655
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Gulley, James L.
中科院分区：
文献类型：
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作者：
Sater, Houssein Abdul;Marte, Jennifer L.;Gulley, James L.
临床试验表明，治疗性疫苗能够对肿瘤相关抗原（TAAs）产生免疫反应。相对不太清楚的是，这是否转化为免疫细胞（IC）浸润到肿瘤微环境中。本研究考察了新辅助前列腺特异性抗原（PSA）靶向PROSTVAC疫苗是否能诱导t细胞免疫，特别是在肿瘤部位。方法一项开放标签、新辅助PROSTVAC疫苗的II期研究纳入了27例等待根治性前列腺切除术（RP）的局限性前列腺癌患者。我们使用六色多重免疫荧光蛋白石法评估CD4和CD8 t细胞浸润的增加（RP组织与基线活检）。抗原特异性反应通过细胞内细胞因子染色评估，在体外刺激外周血单个核细胞后，用重叠的15个肽库编码TAAs PSA、brachyury和MUC-1。结果在27例接种疫苗的患者中，26例有匹配的接种前（活检）和接种后（RP）前列腺样本，可用于非分区分析（NCA）和分区分析（CA）。与NCA基线活检相比，接种后RP标本中肿瘤CD4 t细胞浸润显著增加(中位数176/mm(2) vs 152/mm(2))；IQR 136-317/mm(2) vs 69-284/mm(2)；p = 0.0249;中位数比率1.20；差0.64 - -2.25)。通过CA，肿瘤浸润边缘CD4 t细胞浸润均增加(中位数198/mm(2) vs 151/mm(2))；IQR 123-500/mm(2) vs 85-256/mm(2)；p = 0.042;中位数比率1.44；IQR 0.59-4.17)和CD8 t细胞浸润在肿瘤核心(中位数140/mm(2) vs 105/mm(2))；IQR 91-175/mm(2) vs 83-163/mm(2)；p = 0.036;中位数比值1.25；与基线活检相比，接种后RP标本的IQR为0.88-2.09)。共有13/25的患者（52%）对三种测试的TAAs（非新抗原）中的任何一种产生外周t细胞反应；其中五种对三种抗原中的一种以上有反应。结论新佐剂PROSTVAC可诱导肿瘤免疫反应和外周免疫反应。
Background Clinical trials have shown the ability of therapeutic vaccines to generate immune responses to tumor-associated antigens (TAAs). What is relatively less known is if this translates into immune-cell (IC) infiltration into the tumor microenvironment. This study examined whether neoadjuvant prostate-specific antigen (PSA)-targeted vaccination with PROSTVAC could induce T-cell immunity, particularly at the tumor site. Methods An open-label, phase II study of neoadjuvant PROSTVAC vaccine enrolled 27 patients with localized prostate cancer awaiting radical prostatectomy (RP). We evaluated increases in CD4 and CD8 T-cell infiltrates (RP tissue vs baseline biopsies) using a six-color multiplex immunofluorescence Opal method. Antigen-specific responses were assessed by intracellular cytokine staining after in vitro stimulation of peripheral blood mononuclear cells with overlapping 15-mer peptide pools encoding the TAAs PSA, brachyury and MUC-1. Results Of 27 vaccinated patients, 26 had matched prevaccination (biopsy) and postvaccination (RP) prostate samples available for non-compartmentalized analysis (NCA) and compartmentalized analysis (CA). Tumor CD4 T-cell infiltrates were significantly increased in postvaccination RP specimens compared with baseline biopsies by NCA (median 176/mm(2) vs 152/mm(2); IQR 136-317/mm(2) vs 69-284/mm(2); p=0.0249; median ratio 1.20; IQR 0.64-2.25). By CA, an increase in both CD4 T-cell infiltrates at the tumor infiltrative margin (median 198/mm(2) vs 151/mm(2); IQR 123-500/mm(2) vs 85-256/mm(2); p=0.042; median ratio 1.44; IQR 0.59-4.17) and in CD8 T-cell infiltrates at the tumor core (median 140/mm(2) vs 105/mm(2); IQR 91-175/mm(2) vs 83-163/mm(2); p=0.036; median ratio 1.25; IQR 0.88-2.09) were noted in postvaccination RP specimens compared with baseline biopsies. A total of 13/25 patients (52%) developed peripheral T-cell responses to any of the three tested TAAs (non-neoantigens); five of these had responses to more than one antigen of the three evaluated. Conclusion Neoadjuvant PROSTVAC can induce both tumor immune response and peripheral immune response.