Immunotherapy Expands and Maintains the Function of High-Affinity Tumor-Infiltrating CD8 T Cells In Situ.
Immunotherapy Expands and Maintains the Function of High-Affinity Tumor-Infiltrating CD8 T Cells In Situ.
复制标题
免疫疗法扩展并维持高亲和力肿瘤浸润的CD8 T细胞的功能。
DOI：
10.4049/jimmunol.1502659
复制
发表时间：
2016-09-15
期刊：
影响因子：
--
通讯作者：
Weinberg AD
中科院分区：
文献类型：
--
作者：
Moran AE;Polesso F;Weinberg AD
癌细胞具有高亲和力的肿瘤相关抗原，能够引发有效的抗肿瘤T细胞反应，但检测这些多克隆T细胞是具有挑战性的。因此，已经使用了T细胞活化的替代标志物，例如CD 69、CD 44和PD-1。我们在这里报告说，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Nur 77 GFP T细胞亲和报告小鼠，我们强调PD-1表达可以独立于肿瘤内的TCR连接而被诱导。鉴于此，我们表征了Nur 77 GFP模型系统在阐明独立于PD-1表达的免疫疗法的作用机制中的效用。Nur 77 GFP和OX 40的共表达鉴定了高亲和力肿瘤相关抗原特异性CD 8 + T细胞的多克隆群体，其原位产生比OX 40阴性更多的IFNγ，并且使用抗OX 40和抗CTLA 4 mAb治疗时数量加倍，但不使用抗PD-1或PD-L1。此外，这些高亲和力CD 8 T细胞的扩增降低了荷瘤动物的存活率。在肿瘤中慢性刺激后和过继性细胞治疗后，CD 8 TCR信号传导和Nur 77 GFP诱导受损，肿瘤进展。然而，这可以逆转，并且在使用激动剂OX 40免疫疗法的过继细胞疗法后，总存活率显著提高。因此，我们提出0X 40激动剂免疫疗法可以维持长期刺激的肿瘤驻留CD 8 T细胞的功能性TCR信号传导，从而增加溶细胞的、高亲和力的、肿瘤相关抗原特异性细胞的频率。
Cancer cells harbor high affinity tumor-associated antigens capable of eliciting potent anti-tumor T cell responses yet detecting these polyclonal T cells is challenging. Therefore, surrogate markers of T cell activation such as CD69, CD44, and PD-1 have been used. We report here that in mice, expression of activation markers including PD-1 is insufficient in the tumor microenvironment to identify tumor-antigen 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. Co-expression of Nur77GFP and OX40 identifies a polyclonal population of high affinity tumor-associated antigen-specific CD8+ T cells, which produce more IFNγ in situ than OX40 negative and doubles in quantity with anti-OX40 and anti-CTLA4 mAb therapy but not with anti-PD-1 or PD-L1. 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 cytolytic, high affinity, tumor-associated antigen-specific cells.
登录
查看更多内容
鉴定人OX-40配体，这是具有与肿瘤坏死因子同源的CD4+ T细胞的costimulator。
影响因子：
15.3
作者：
Godfrey, Wayne R.;Fagnoni, Francesco F.;Haraa, Marwan A.;Buck, David;Engleman, Edgar G.
通讯作者：
Engleman, Edgar G.
DOI：
10.1073/pnas.1413726111
发表时间：
2014-09-02
影响因子：
11.1
作者：
Au-Yeung, Byron B.;Zikherman, Julie;Weiss, Arthur
通讯作者：
Weiss, Arthur
影响因子：
4.4
作者：
Liu, F;Whitton, JL
通讯作者：
Whitton, JL
影响因子：
3.9
作者：
ALEXANDER, RB;FITZGERALD, EB;ROSENBERG, SA
通讯作者：
ROSENBERG, SA
影响因子：
30.5
作者：
Kaech, SM;Ahmed, R
通讯作者：
Ahmed, R