Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Department of Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan
J Immunother Cancer. 2024 Nov 3;12(11):e010174. doi: 10.1136/jitc-2024-010174.
Gastric cancer (GC) is one of the most common and deadly malignant diseases worldwide. Despite revolutionary advances, the therapeutic efficacy of anti-PD1/PDL1 monoclonal antibodies in advanced GC is still low due to the emergence of innate and acquired resistance to treatment. Myeloid cells represent the majority of human immune cells. Therefore, their increase, decrease, and abnormality could have a significant impact on the patient's immune system and the progression of cancer, and reprogramming, inhibiting, and eliminating the tumor-supportive types may improve the immunological situation and efficacy of immunotherapy. However, the significance of myeloid cells in anti-PD1/PDL1 therapy remains unclear in GC. In the WJOG10417GTR study on GC, we sought to identify myeloid determinants that could predict anti-PD1 therapeutic efficacy and also serve as potential therapeutic targets.
We collected tumor tissues and peripheral blood from 96 patients with advanced GC before and 1 month after anti-PD1 nivolumab monotherapy, and the isolated whole leucocytes were analyzed by flow cytometry for various immune cell populations, including many myeloid subsets. Then, the relationship between the cellular levels and progression-free survival (PFS) or overall survival (OS) was statistically analyzed.
We found that high levels of several myeloid subsets expressing molecules that have been targeted in drug discovery but not yet approved for clinical use were significantly associated with shorter PFS/OS as compared with low levels: PDL1 and CTLA4 myeloid subsets within tumors at baseline, PDL1, B7H3 and CD115 myeloid subsets in peripheral blood at baseline, and LAG3, CD155 and CD115 myeloid subsets in peripheral blood at post-treatment.
This study revealed that these myeloid subsets are significant risk factors in nivolumab therapy for advanced GC. Targeting them may be useful as diagnostic biomarkers to predict potential anti-PD1 therapeutic efficacy, and also as therapeutic targets for accelerating the development of new drugs to improve clinical outcomes in immunotherapy for GC.
胃癌（GC）是全球最常见和最致命的恶性疾病之一。尽管取得了革命性的进展，但由于对治疗产生先天和获得性耐药，抗 PD1/PDL1 单克隆抗体在晚期 GC 中的治疗效果仍然较低。髓样细胞代表了人类免疫细胞的大多数。因此，它们的增加、减少和异常可能对患者的免疫系统和癌症的进展产生重大影响，重新编程、抑制和消除肿瘤支持型细胞可能会改善免疫状况和免疫治疗的效果。然而，髓样细胞在 GC 中抗 PD1/PDL1 治疗中的意义仍不清楚。在 GC 的 WJOG10417GTR 研究中，我们试图确定能够预测抗 PD1 治疗效果的髓样决定因素，这些因素也可能成为潜在的治疗靶点。
我们收集了 96 例晚期 GC 患者在抗 PD1 单药 nivolumab 治疗前后的肿瘤组织和外周血，并通过流式细胞术分析分离的全白细胞中的各种免疫细胞群体，包括许多髓样亚群。然后，对细胞水平与无进展生存期（PFS）或总生存期（OS）之间的关系进行了统计学分析。
我们发现，与低水平相比，表达药物发现中已靶向但尚未批准临床使用的分子的几种髓样亚群的高水平与较短的 PFS/OS 显著相关：基线时肿瘤内的 PDL1 和 CTLA4 髓样亚群、基线时外周血中的 PDL1、B7H3 和 CD115 髓样亚群以及治疗后外周血中的 LAG3、CD155 和 CD115 髓样亚群。
这项研究表明，这些髓样亚群是晚期 GC 中 nivolumab 治疗的重要危险因素。针对这些髓样亚群可能有助于作为诊断生物标志物来预测潜在的抗 PD1 治疗效果，也有助于作为治疗靶点，加速开发新药，以改善 GC 免疫治疗的临床结果。
