瑞士实验癌症研究所（ISREC）Douglas Hanahan和Stephan Wullschleger共同合作，近期取得重要工作进展。他们研究发现双特异性PD1-IL2v和抗PD-L1通过增强干样肿瘤反应性CD8⁺ T细胞和重编程巨噬细胞来打破肿瘤免疫抵抗。相关研究成果2023年1月10日在线发表于《免疫学》杂志上。

据介绍，免疫疗法在临床上显示出显著的治疗效果，尽管是肿瘤选择性的。大多数患者的反应最多是短暂的，这突出了理解耐药机制的重要性。

研究人员评估了工程免疫细胞因子PD1-IL2v在新发胰腺神经内分泌癌小鼠模型中的作用，该模型对检查点和其他免疫疗法具有耐药性。PD1-IL2v利用抗PD-1作为与免疫刺激性IL-2细胞因子变体（IL2v）融合的靶向部分，将IL2v精确递送至肿瘤微环境中的PD-1⁺ T细胞。PD1-IL2v诱导干细胞样CD8⁺ T细胞大量浸润，导致小鼠肿瘤消退并提高存活率。抗PD-L1和PD1-IL2v联合使用维持了反应期，通过重新编程免疫抑制肿瘤相关巨噬细胞和增强T细胞受体（TCR）免疫库多样性提高了治疗效果。

总之，这些数据为临床试验评估PD1-IL2v和抗PD-L1的联合治疗提供了理论依据，特别是在浸润有PD-1⁺干细胞样T细胞浸润的免疫治疗耐药肿瘤中。

附：英文原文

Title: Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8+ T cells and reprogramming macrophages

Author: Mélanie Tichet, Stephan Wullschleger, Agnieszka Chryplewicz, Nadine Fournier, Rachel Marcone, Annamaria Kauzlaric, Krisztian Homicsko, Laura Codarri Deak, Pablo Umaa, Christian Klein, Douglas Hanahan

Issue&Volume: 2023/01/10

Abstract: Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most patients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects of the engineered immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer that is resistant to checkpoint and other immunotherapies. PD1-IL2v utilizes anti-PD-1 as a targeting moiety fused to an immuno-stimulatory IL-2 cytokine variant (IL2v) to precisely deliver IL2v to PD-1+ T cells in the tumor microenvironment. PD1-IL2v elicited substantial infiltration by stem-like CD8+ T cells, resulting in tumor regression and enhanced survival in mice. Combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and enhancing T cell receptor (TCR) immune repertoire diversity. These data provide a rationale for clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, particularly in immunotherapy-resistant tumors infiltrated with PD-1+ stem-like T cells.

DOI: 10.1016/j.immuni.2022.12.006

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00642-2