小柯机器人

美国埃默里大学医学院Rafi Ahmed研究组发现，PD-1与IL-2联合治疗改变CD8+T细胞的耗竭程序。这一研究成果于2022年9月28日在线发表在国际学术期刊《自然》上。

在慢性淋巴细胞性脉络膜炎病毒感染期间，PD-1阻断和IL-2的联合治疗非常有效。研究人员揭示了这种协同作用的根本基础。研究人员表明，与PD-1单药治疗相比，PD-1+IL-2联合治疗大大改变了PD-1⁺TCF1⁺干细胞样CD8⁺T细胞的分化程序，并导致产生转录和表观遗传上不同的效应型CD8⁺T细胞，与急性病毒感染后看到的高功能效应型CD8⁺T细胞相似。这些优异的CD8⁺T细胞介导病毒控制是PD-1和IL-2之间协同作用的基础。研究结果表明，PD-1⁺TCF1⁺干细胞样CD8⁺T细胞，也被称为耗竭型CD8⁺T细胞的前体，并没有被锁定在耗竭程序中，其分化轨迹可以被IL-2信号改变。

联合治疗后，这些从干细胞样CD8⁺T细胞中出现的病毒特异性效应CD8⁺T细胞表达的高亲和力IL-2三聚体（CD25-CD122-CD132）受体水平增加。这在单独阻断PD-1后没有看到。最后，研究人员表明，CD25与IL-2的接触在观察到的IL-2细胞因子和PD-1阻断之间的协同作用中具有重要作用。无论是用抗体阻断CD25，还是使用不与CD25结合但仍与CD122和CD132结合的突变版IL-2，都几乎完全废除了PD-1+IL-2联合治疗后观察到的协同作用。人们对癌症患者的PD-1+IL-2联合治疗相当感兴趣，这些基础研究界定了IL-2如何与PD-1阻断协同作用的基本机制，有望为这些人类转化研究提供参考。

附：英文原文

Title: PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program

Author: Hashimoto, Masao, Araki, Koichi, Cardenas, Maria A., Li, Peng, Jadhav, Rohit R., Kissick, Haydn T., Hudson, William H., McGuire, Donald J., Obeng, Rebecca C., Wieland, Andreas, Lee, Judong, McManus, Daniel T., Ross, James L., Im, Se Jin, Lee, Junghwa, Lin, Jian-Xin, Hu, Bin, West, Erin E., Scharer, Christopher D., Freeman, Gordon J., Sharpe, Arlene H., Ramalingam, Suresh S., Pellerin, Alex, Teichgrber, Volker, Greenleaf, William J., Klein, Christian, Goronzy, Jorg J., Umaa, Pablo, Leonard, Warren J., Smith, Kendall A., Ahmed, Rafi

Issue&Volume: 2022-09-28

Abstract: Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25–CD122–CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.

DOI: 10.1038/s41586-022-05257-0

Source: https://www.nature.com/articles/s41586-022-05257-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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