Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
Mol Cancer. 2024 Aug 20;23(1):169. doi: 10.1186/s12943-024-02085-w.
In the KEYNOTE-811 study, anti-HER2 and immunotherapy treatments resulted in longer survival in HER2-positive gastric cancer patients with CPS ≥ 1, whereas CPS < 1 patients lacked notable benefits. We studied this in a real-world cohort of 106 HER2-positive, CPS < 1 patients and found no survival differences between those treated with anti-HER2 therapy alone or with added immunotherapy. Thus, we investigate the tumor microenvironment variations in 160 HER2-positive patients, CPS ≥ 1 cases exhibited elevated spatial effective scores of immune cells, including CD4, CD8 subtypes, and NK cells, compared to CPS < 1. Furthermore, through single-cell sequencing in eight HER2-positive individuals, gene expressions revealed regulation of T-cell co-stimulation in CPS ≥ 1 and IL-1 binding in CPS < 1 cases. Notably, we discovered a CPS < 1 subtype marked by CXCR4M2 macrophages, associated with poor prognosis, whose proportion and expression were reduced when benefiting from anti-HER2 therapy. These findings suggest CPS ≥ 1 patients, due to their immune microenvironment composition, may respond better to anti-PD-1/PD-L1 therapy.
在 KEYNOTE-811 研究中，抗 HER2 和免疫疗法治疗在 CPS≥1 的 HER2 阳性胃癌患者中导致生存时间延长，而 CPS<1 的患者则缺乏明显获益。我们在 106 例 HER2 阳性、CPS<1 的真实队列中研究了这一点，发现抗 HER2 治疗联合或不联合免疫治疗的患者之间的生存无差异。因此，我们调查了 160 例 HER2 阳性患者的肿瘤微环境变化，与 CPS<1 的患者相比，CPS≥1 的患者的免疫细胞空间有效评分升高，包括 CD4、CD8 亚型和 NK 细胞。此外，通过对 8 例 HER2 阳性个体的单细胞测序，基因表达揭示了 CPS≥1 中 T 细胞共刺激的调节和 CPS<1 中 IL-1 结合的调节。值得注意的是，我们发现了一种以 CXCR4M2 巨噬细胞为标志的 CPS<1 亚型，与预后不良相关，当受益于抗 HER2 治疗时，其比例和表达减少。这些发现表明，由于其免疫微环境组成，CPS≥1 的患者可能对抗 PD-1/PD-L1 治疗反应更好。
