小柯机器人

瑞士罗氏苏黎世创新中心Pablo Umaña、Christian Klein等研究人员合作发现，PD-1-顺式IL-2R激动作用可从干性样CD8+T细胞中获得更好的效应细胞。这一研究成果于2022年9月28日发表在国际顶尖学术期刊《自然》上。

研究人员表示，抗原经历的PD-1⁺TCF-1⁺干细胞样CD8⁺T细胞会扩增和分化为效应细胞，这对基于PD-1阻断的免疫疗法的成功至关重要。Hashimoto等人表明，在慢性感染中，细胞因子白细胞介素（IL）-2的施用引发了干细胞样T细胞的另一种分化路径，使其成为类似于急性感染中产生的“更好的效应”CD8⁺T细胞的独特群体。IL-2与IL-2受体α链（CD25）的结合对于触发这种替代性分化途径和扩大具有独特转录和表观遗传特征的更好的效应器是至关重要的。然而，CD25在调节性T细胞和一些内皮细胞上的构成性表达也有助于IL-2疗法产生不需要的全身效应。因此，目前正在开发工程化的IL-2受体β链和γ链（IL-2Rβγ）偏向性激动剂。

研究人员表明，基于IL-2Rβγ的激动剂不能在癌症模型中优先扩大更好的效应T细胞，并描述了PD1-IL2v，一种新的免疫细胞因子，通过与PD-1顺向对接克服了CD25结合的需要。在慢性感染和癌症模型中，PD1-IL2v与PD-1和IL-2Rβγ顺式结合，在没有CD25结合的情况下，恢复了将干细胞样CD8⁺T细胞分化为更好效应细胞的能力，并提供了优越的疗效。相比之下，单独的PD-1或PD-L1阻断抗体，或其与临床相关剂量的非PD-1靶向IL2v的组合，不能扩大这种独特且更好的效应T细胞亚群，而是导致终末分化、耗尽的T细胞积累。这些发现为开发新一代PD-1顺式靶向IL-2R激动剂提供了基础，该激动剂在治疗癌症和慢性感染方面具有更强的治疗潜力。

附：英文原文

Title: PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells

Author: Codarri Deak, Laura, Nicolini, Valeria, Hashimoto, Masao, Karagianni, Maria, Schwalie, Petra C., Lauener, Laura, Varypataki, Eleni Maria, Richard, Marine, Bommer, Esther, Sam, Johannes, Joller, Stefanie, Perro, Mario, Cremasco, Floriana, Kunz, Leo, Yanguez, Emilio, Hsser, Tamara, Schlenker, Ramona, Mariani, Marisa, Tosevski, Vinko, Herter, Sylvia, Bacac, Marina, Waldhauer, Inja, Colombetti, Sara, Gueripel, Xavier, Wullschleger, Stephan, Tichet, Melanie, Hanahan, Douglas, Kissick, Haydn T., Leclair, Stephane, Freimoser-Grundschober, Anne, Seeber, Stefan, Teichgrber, Volker, Ahmed, Rafi, Klein, Christian, Umaa, Pablo

Issue&Volume: 2022-09-28

Abstract: Expansion and differentiation of antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1,2,3,4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of ‘better effector’ CD8+ T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed6,7,8,9,10. Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8+ T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

DOI: 10.1038/s41586-022-05192-0

Source: https://www.nature.com/articles/s41586-022-05192-0

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
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html