Nishioka Naoya, Naito Tateaki, Sugino Takashi, Muramatsu Koji, Nishihara Shigeki, Urashima Hiroki, Mamesaya Nobuaki, Kobayashi Haruki, Omori Shota, Ko Ryo, Wakuda Kazushige, Ono Akira, Kenmotsu Hirotsugu, Murakami Haruyasu, Takahashi Toshiaki
Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Thorac Cancer. 2025 May;16(10):e70089. doi: 10.1111/1759-7714.70089.
Serum growth/differentiation factor 15 (GDF-15) suppresses anti-tumor immunity and predicts prognosis in several malignancies. Elevated GDF-15 levels are linked to cancer cachexia, characterized by weight loss and systemic inflammation, adversely affecting patient outcomes and therapy response. However, serum GDF-15 is not always derived from tumor tissues but also from multiple organs. Therefore, we evaluated whether intra-tumoral GDF-15 could be used as a biomarker for immunotherapy and its potential association with cancer cachexia.
We retrospectively evaluated patients with advanced non-small cell lung cancer (NSCLC) who underwent treatment with programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors at the Shizuoka Cancer Center between 2017 and 2021. Patients with histologically confirmed NSCLC (stage III-IV or postoperative recurrence) who had undergone biopsy or surgery within 6 months prior to initiating immunotherapy were included. Expression of tumor-derived GDF-15 was evaluated using immunohistochemical staining of archival biopsy and surgical specimens. We analyzed the correlation between intra-tumoral GDF-15 expression and the incidence of cancer cachexia, as well as its impact on progression-free survival (PFS) and overall survival (OS).
In 6 of 35 cases, tumor cells highly expressed GDF-15. Patients with high intra-tumoral GDF-15 expression had a higher incidence of cancer cachexia (100% vs. 41.4%, p < 0.05), shorter PFS (3.4 vs. 13.4 months, p < 0.05), and shorter OS (9.5 vs. 26.5 months, p < 0.05) than those with low intra-tumoral GDF-15 expression.
Intra-tumoral GDF-15 expression may predict the presence of cancer cachexia and the efficacy of PD-1/PD-L1 inhibitors in patients with advanced non-small cell lung cancer.
血清生长/分化因子15（GDF-15）可抑制抗肿瘤免疫，并可预测多种恶性肿瘤的预后。GDF-15水平升高与癌症恶病质相关，其特征为体重减轻和全身炎症，对患者的预后和治疗反应产生不利影响。然而，血清GDF-15并非总是来源于肿瘤组织，也可来源于多个器官。因此，我们评估了肿瘤内GDF-15是否可作为免疫治疗的生物标志物及其与癌症恶病质的潜在关联。
我们回顾性评估了2017年至2021年期间在静冈癌症中心接受程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡配体1（PD-L1）抑制剂治疗的晚期非小细胞肺癌（NSCLC）患者。纳入在开始免疫治疗前6个月内接受过活检或手术、组织学确诊为NSCLC（III-IV期或术后复发）的患者。使用存档活检和手术标本的免疫组织化学染色评估肿瘤源性GDF-15的表达。我们分析了肿瘤内GDF-15表达与癌症恶病质发生率之间的相关性，以及其对无进展生存期（PFS）和总生存期（OS）的影响。
35例患者中有6例肿瘤细胞高表达GDF-15。肿瘤内GDF-15高表达的患者比肿瘤内GDF-15低表达的患者癌症恶病质发生率更高（100%对41.4%，p<0.05），PFS更短（3.4个月对13.4个月，p<0.05），OS更短（9.5个月对26.5个月，p<0.05）。
肿瘤内GDF-15表达可能预测晚期非小细胞肺癌患者癌症恶病质的存在以及PD-1/PD-L1抑制剂的疗效。
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