Desensitizing Effect of Intra-Tumoral GDF-15 on Immunotherapy in Patients With Advanced Non-Small Cell Lung Cancer.

BACKGROUND: 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. METHOD: 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). RESULT: 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. CONCLUSION: 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.