Negative effect of malignant pleural effusion on the efficacy of immunotherapy via IL-6–mediated abscopal immunosuppression in advanced non-small cell lung cancer.

12059 Background: The present study is designed to determine the effect and mechanism of malignant pleural effusion (MPE) on the efficacy of immunotherapy in advanced non-small cell lung cancer (NSCLC). Methods: We identified patients with advanced NSCLC who underwent immunotherapy as a first-line or second-line regimen in multiple cohorts. The objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and overall survival (OS) were analyzed. Using a mouse model with MPE, we determined whether MPE could affect the efficacy of immunotherapy and investigated the mechanism of MPE-related immunosuppression. Results: In a cohort with 269 advanced NSCLC patients who received PD-1 inhibitor alone or combined chemotherapy, MPE occurred in 82 (30.5%) patients. Patients with MPE had a shorter median PFS (4.0 vs. 9.8 months) and OS (21.0 vs. 29.9 months) than those without MPE. MPE was an independent factor affecting PFS (HR:1.87) and OS (HR: 2.73). The ORR for patients with and without MPE was 20% and 34%, respectively. In another cohort with 69 advanced NSCLC patients with MPE who receive PD-1 inhibitor plus chemotherapy plus bevacizumab or PD-1 inhibitor plus chemotherapy, there was no significant difference in median PFS (19.1 vs. 13.2 months) and OS (21.8 vs. 21.6 months), ORR (42.1% vs. 36.8%,), and extrapleural ORR (23.9% vs. 26.3%) between the two groups. In addition, IL-6 levels in serum and pleural effusions were significantly higher in NSCLC patients with MPE. Furthermore, in a mouse tumor MPE model by subcutaneous and pleural injection of lung cancer cells, PD-1 inhibitor did not decrease tumor growth and prolong survival in MPE-bearing mice. Immunohistochemistry and flow cytometry demonstrated the proportion of CD3 + T cells, CD4 + T cells and CD8 + T cells were decreased in the subcutaneous tumors with MPE. Dural blockade with PD-1 inhibitor and IL-6 receptor antibody inhibited tumor growth and prolonged survival of MPE-bearing mice. Conclusions: The occurrence of MPE is negatively correlated with patient outcomes when receiving PD-1 inhibitor or PD-1 inhibitor plus bevacizumab. Elevated IL-6 levels may be responsible for abscopal inhibitory tumor immune microenvironment and reduced efficacy of immunotherapy. Dural blockade of PD-1 and IL-6 could be a promising therapeutic strategy for advanced NSCLC with MPE.