肿瘤细胞治疗研究
英文原题：Exploration of Immune-Modulatory Effects of Amivantamab in Combination with Pembrolizumab in Lung and Head and Neck Squamous Cell Carcinoma.
我们证明，单用pembrolizumab或amivantamab均无效，而联合治疗在两种模型中均显著抑制肿瘤生长（分别为P < 0.0001和P < 0.01）。
免疫检查点抑制剂是实体癌的有效一线治疗。然而，低应答率和随时间推移产生的获得性耐药促使人们需要额外的治疗选择。在此，我们在头颈部鳞状细胞癌（HNSCC）和肺鳞状细胞癌荷瘤人源化患者来源异种移植（PDX）模型中，评估了靶向EGFR × MET的双特异性抗体amivantamab与PD-L1免疫治疗药物pembrolizumab的协同抗肿瘤疗效。我们证明，单用pembrolizumab或amivantamab无效，而联合治疗在两种模型中均显著抑制了肿瘤生长（分别为P < 0.0001和P < 0.01）。联合使用amivantamab和pembrolizumab似乎显著增强了HNSCC PDX的TME中产生颗粒酶B的CD8 T细胞浸润（P < 0.01），并增强了循环免疫细胞中与新抗原相关的中枢记忆CD8 T细胞。单细胞RNA转录组学分析提示，肿瘤细胞在PD-L1免疫治疗作用下显著上调EGFR和MET，可能形成适合肿瘤在肿瘤微环境（TME）中持续存在的代谢状态，并使pembrolizumab失效。我们证明，与EGFRLOWMETLOW簇相比，EGFRHIGHMETHIGH亚簇显示与乳酸生成相关的基因[SLC16A3和乳酸脱氢酶A（LDHA）]表达增加。TME中乳酸的积累通过阻碍肿瘤杀伤性CD8 T细胞和NK细胞的浸润而与免疫抑制相关。本研究证明，amivantamab降低了EGFRHIGHMETHIGH亚群中的糖酵解标志物，包括SLC16A3和LDHA，并强调了联合治疗对TME的重塑，为amivantamab联合PD-1免疫治疗提供了依据。意义：amivantamab与pembrolizumab协同作用，有效清除了头颈部鳞状细胞癌肿瘤微环境中的EGFRHIGHMETHIGH肿瘤亚群，并克服了对抗PD-1免疫治疗的耐药性。
UNLABELLED: Immune checkpoint inhibitors are effective first-line therapy for solid cancers. However, low response rate and acquired resistance over time has led to the need for additional therapeutic options. Here, we evaluated synergistic antitumor efficacy of EGFR × MET targeting bispecific antibody, amivantamab with PD-L1 immunotherapy, pembrolizumab in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma tumor-bearing humanized patient-derived xenograft (PDX) models. We demonstrated that pembrolizumab or amivantamab alone was ineffective and that combination treatment induced a significant reduction of tumor growth in both models (P < 0.0001 and P < 0.01, respectively). It appeared that combination of amivantamab and pembrolizumab significantly enhanced infiltration of granzyme B-producing CD8 T cells was in the TME of HNSCC PDX (P < 0.01) and enhanced neoantigen-associated central memory CD8 T cells in circulating immune cells. Analysis of single-cell RNA transcriptomics suggested that the tumor cells dramatically upregulated EGFR and MET in response to PD-L1 immunotherapy, potentially creating a metabolic state fit for tumor persistence in the tumor microenvironment (TME) and rendered pembrolizumab ineffective. We demonstrated that EGFRHIGHMETHIGH subcluster displayed an increased expression of genes implicated in production of lactate [SLC16A3 and lactate dehydrogenase A (LDHA)] compared to the EGFRLOWMETLOW cluster. Accumulation of lactate in the TME has been associated with immunosuppression by hindering the infiltration of tumor killing CD8 T and NK cells. This study proved that amivantamab reduced glycolytic markers in the EGFRHIGHMETHIGH subcluster including SLC16A3 and LDHA and highlighted remodeling of the TME by combination treatment, providing rationale for additional therapy of amivantamab with PD-1 immunotherapy. SIGNIFICANCE: Amivantamab in synergy with pembrolizumab effectively eradicated EGFRHIGHMETHIGH tumor subcluster in the tumor microenvironment of head and neck squamous cell carcinoma and overcame resistance against anti-PD-1 immunotherapy.
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