Department of Urology; College of Medicine; Mayo Clinic; Rochester, MN USA.
Oncoimmunology. 2013 Jun 1;2(6):e23972. doi: 10.4161/onci.23972. Epub 2013 Jun 6.
Immunotherapies aimed at enhancing natural or endogenous antitumor T-cell immunity in patients affected by advanced malignancies are currently being implemented in the clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, reliable biomarkers are needed. We used CD11a, an integrin that is upregulated on the surface of effector and memory CD8 T cells, and PD-1, an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantify and monitor endogenous tumor-reactive cytotoxic T lymphocytes (CTLs) in two mouse tumor models and in the peripheral blood of 12 patients affected by Stage IV melanoma. High expression levels of CD11a and PD-1 were detected among CD8 T cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the peripheral blood of melanoma patients, tumor antigen-specific CD8 T cells were associated with a population of CD11a CD8 T cells that co-expressed high levels of PD-1. Healthy donors exhibited a comparatively much lower frequency of such PD-1CD11aCD8 T cells. Phenotypic analyses demonstrated that CD11aCD8 T cells are proliferating (Ki67) and activated (CD62LCD69). Increased CD11aCD8 T cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector functions of CD8 T cells is compromised by an elevated expression of PD-1. The CD11aCD8 T-cell population expresses high levels of PD-1 and presumably constitutes the cellular target of PD-1 blockade therapy. The expression level of CD11a and PD-1 by CD8 T cells may therefore represent a novel biomarker to identify and monitor endogenous tumor-reactive CTLs. This may not only provide an immunological readout for evaluating the efficacy of immunotherapy but also contribute to the selection of cancer patients who are likely to benefit from anti-PD-1 therapy.
免疫疗法旨在增强受晚期恶性肿瘤影响的患者体内天然或内源性抗肿瘤 T 细胞免疫，目前正在临床中实施，并取得了有前景的结果。为了优化治疗方案并监测这些疗法的有效性，需要可靠的生物标志物。我们使用 CD11a，这是一种在效应器和记忆性 CD8 T 细胞表面上调的整合素，以及 PD-1，一种在激活的 T 细胞上表达的免疫调节受体，作为生物标志物来识别、定量和监测两种小鼠肿瘤模型和 12 名 IV 期黑色素瘤患者外周血中的内源性肿瘤反应性细胞毒性 T 淋巴细胞 (CTL)。在原发性和转移性小鼠肿瘤部位以及自发的小鼠乳腺癌组织中，CD8 T 细胞中检测到 CD11a 和 PD-1 的高表达。在黑色素瘤患者的外周血中，肿瘤抗原特异性 CD8 T 细胞与一群表达高水平 PD-1 的 CD11a CD8 T 细胞相关。健康供体表现出相对低得多的这种 PD-1 CD11a CD8 T 细胞频率。表型分析表明 CD11a CD8 T 细胞正在增殖 (Ki67) 和激活 (CD62L CD69)。在 PD-1 缺陷小鼠中观察到 CD11a CD8 T 细胞增加和肿瘤生长延迟，表明 CD8 T 细胞的抗肿瘤效应功能因 PD-1 的高表达而受损。CD11a CD8 T 细胞群表达高水平的 PD-1，推测其构成 PD-1 阻断治疗的细胞靶标。因此，CD8 T 细胞的 CD11a 和 PD-1 表达水平可能代表识别和监测内源性肿瘤反应性 CTL 的新型生物标志物。这不仅为评估免疫疗法的疗效提供了免疫学指标，还有助于选择可能受益于抗 PD-1 治疗的癌症患者。
