Jiang Jiayun, Zhang Hui, Ou Yanjiao, Lai Jiejuan, Huang Yulan, Cai Wenyun, Li Chong, Zhang Leida, Fu Yu
Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University/Army Medical University, Chongqing, 400038, PR China.
Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China.
Immunol Lett. 2025 Oct;275:107003. doi: 10.1016/j.imlet.2025.107003. Epub 2025 Apr 4.
Despite encouraging clinical benefits have gained by anti-PD-1 and Lenvatinib combination, in-depth characterizations about the mechanisms of action remain poorly characterized. Furthermore, although the combination of systemic anti-PD-1 or Lenvatinib treatment and locoregional transcatheter arterial chemoembolization (TACE) is widely carried out to treat unresectable HCC in clinical, the efficacies of different combination regimens are uncertain due to limited researches.
We firstly generated murine HCC models to validate the enhanced anti-tumor effects of anti-PD-1 and Lenvatinib combination therapy. Then single cell mass cytometry (CyTOF) was employed to phenotypically reveal their mechanisms of action. After that, we further compared the effectiveness of TACE plus Lenvatinib (i.e., TACE-Len) dual therapy with TACE, Lenvatinib plus anti-PD-1 (i.e., TACE-Len-PD-1) triple therapy as conversion therapy for unresectable HCC.
Lenvatinib and anti-PD-1 combination could generate activated immune profiles not only by increasing systemic CD4, CD8T cells and B cells proportions, but also by weakening the immune-tolerance functions derived from both immunosuppressive cells (i.e., MDSCs) and co-inhibitory mediators (i.e., PD-L1 and LAG-3). Meanwhile, our study also suggested that TACE-Len-PD-1 triple therapy could achieve better clinical responses with powerful immune profiles for unresectable HCC compared to TACE-Len dual therapy.
Our study provided a delicate immune landscape of anti-PD-1and Lenvatinib combination, and we also offered scientific evidences that TACE-Len-PD-1 triple therapy could fulfill better clinical benefits than TACE-Len dual therapy, which is anticipated to provide objective and effective evidences for clinical use.
尽管抗PD - 1与乐伐替尼联合治疗已取得令人鼓舞的临床益处，但对其作用机制的深入研究仍显不足。此外，虽然在临床中广泛采用全身抗PD - 1或乐伐替尼治疗与局部经动脉化疗栓塞术（TACE）联合来治疗不可切除的肝癌，但由于研究有限，不同联合方案的疗效尚不确定。
我们首先构建小鼠肝癌模型以验证抗PD - 1与乐伐替尼联合治疗增强的抗肿瘤效果。然后采用单细胞质谱流式细胞术（CyTOF）从表型上揭示其作用机制。之后，我们进一步比较了TACE联合乐伐替尼（即TACE - Len）双药治疗与TACE、乐伐替尼联合抗PD - 1（即TACE - Len - PD - 1）三药治疗作为不可切除肝癌转化治疗的效果。
乐伐替尼与抗PD - 1联合不仅可通过增加全身CD4、CD8 T细胞和B细胞比例产生激活的免疫图谱，还可通过削弱免疫抑制细胞（即骨髓来源的抑制细胞，MDSCs）和共抑制介质（即PD - L1和LAG - 3）衍生的免疫耐受功能来实现。同时，我们的研究还表明，与TACE - Len双药治疗相比，TACE - Len - PD - 1三药治疗对不可切除肝癌可实现更好的临床反应，并具有强大的免疫图谱。
我们的研究提供了抗PD - 1与乐伐替尼联合治疗精细的免疫图景，并且我们还提供了科学证据表明TACE - Len - PD - 1三药治疗比TACE - Len双药治疗可带来更好的临床益处，有望为临床应用提供客观有效的证据。
