Moran Amy E, Polesso Fanny, Weinberg Andrew D
Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Portland Providence Medical Center, Portland, OR 97213
Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Portland Providence Medical Center, Portland, OR 97213.
J Immunol. 2016 Sep 15;197(6):2509-21. doi: 10.4049/jimmunol.1502659. Epub 2016 Aug 8.
Cancer cells harbor high-affinity tumor-associated Ags capable of eliciting potent antitumor T cell responses, yet detecting these polyclonal T cells is challenging. Therefore, surrogate markers of T cell activation such as CD69, CD44, and programmed death-1 (PD-1) have been used. We report in this study that in mice, expression of activation markers including PD-1 is insufficient in the tumor microenvironment to identify tumor Ag-specific T cells. Using the Nur77GFP T cell affinity reporter mouse, we highlight that PD-1 expression can be induced independent of TCR ligation within the tumor. Given this, we characterized the utility of the Nur77GFP model system in elucidating mechanisms of action of immunotherapies independent of PD-1 expression. Coexpression of Nur77GFP and OX40 identifies a polyclonal population of high-affinity tumor-associated Ag-specific CD8(+) T cells, which produce more IFN-γ in situ than OX40 negative and doubles in quantity with anti-OX40 and anti-CTLA4 mAb therapy but not with anti-PD-1 or programmed death ligand-1. Moreover, expansion of these high-affinity CD8 T cells prolongs survival of tumor-bearing animals. Upon chronic stimulation in tumors and after adoptive cell therapy, CD8 TCR signaling and Nur77GFP induction is impaired, and tumors progress. However, this can be reversed and overall survival significantly enhanced after adoptive cell therapy with agonist OX40 immunotherapy. Therefore, we propose that OX40 agonist immunotherapy can maintain functional TCR signaling of chronically stimulated tumor-resident CD8 T cells, thereby increasing the frequency of cytotoxic, high-affinity, tumor-associated Ag-specific cells.
癌细胞含有能够引发强效抗肿瘤T细胞反应的高亲和力肿瘤相关抗原，但检测这些多克隆T细胞具有挑战性。因此，已使用T细胞活化的替代标志物，如CD69、CD44和程序性死亡-1（PD-1）。我们在本研究中报告，在小鼠中，包括PD-1在内的活化标志物在肿瘤微环境中的表达不足以识别肿瘤抗原特异性T细胞。使用Nur77GFP T细胞亲和力报告小鼠，我们强调PD-1表达可在肿瘤内独立于TCR连接而被诱导。鉴于此，我们表征了Nur77GFP模型系统在阐明独立于PD-1表达的免疫治疗作用机制方面的效用。Nur77GFP和OX40的共表达鉴定出一群多克隆的高亲和力肿瘤相关抗原特异性CD8(+) T细胞，它们在原位产生的IFN-γ比OX40阴性细胞更多，并且在用抗OX40和抗CTLA4单克隆抗体治疗后数量增加一倍，但用抗PD-1或程序性死亡配体-1治疗则不然。此外，这些高亲和力CD8 T细胞的扩增延长了荷瘤动物的生存期。在肿瘤中慢性刺激后以及过继性细胞治疗后，CD8 TCR信号传导和Nur77GFP诱导受损，肿瘤进展。然而，在用激动剂OX40免疫疗法进行过继性细胞治疗后，这可以被逆转，并且总生存期显著延长。因此，我们提出OX40激动剂免疫疗法可以维持慢性刺激的肿瘤驻留CD8 T细胞的功能性TCR信号传导，从而增加细胞毒性、高亲和力、肿瘤相关抗原特异性细胞的频率。
