Prognostic significance of pleural effusion exhausted CD8+ T cell subsets in non-small cell lung cancer and mesothelioma.

Abstract

e21111 Background: Following repeated tumor antigen stimulation, T cells lose functional capacity and become exhausted. T cell exhaustion is a progressive change in phenotype. Early in the pathway, stem-like exhausted T cells (Texstem) retain proliferative and cytotoxic potential. However, they differentiate into terminally exhausted T cells (Texterm) that become epigenetically fixed in a suppressed state and lose much of their effector function. Malignant pleural effusion is a peri-tumoral microenvironment that could offer insight into anti-tumor immune responses. In this study we characterized exhausted CD8+ T cells, examined the prognostic significance of Texstem and Texterm levels in the pleural effusions of patients with non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort. Methods: Pre-treatment malignant pleural effusions from 43 NSCLC (41 non-squamous and 2 squamous) and 50 mesothelioma patients were analyzed by flow cytometry. The percentages of Texstem (PD1midCD39- or PD1midCD39-CD28+) and Texterm (PD1hi CD39+) CD8+ T cells were correlated with overall survival (OS). Survival analysis was performed using Kaplan-Meier and multivariate Cox regression analysis adjusting for age, sex, histological and molecular subtypes, performance status, smoking history, comorbidities and the number of lines of systemic therapy. Results: The relative percentages of exhausted T cells within the CD8+ T cell compartment of pleural effusions from NSCLC and mesothelioma were similar (Table). In NSCLC patients, multivariate analysis demonstrated that the percentage of Texstem was an independent predictor of OS. The median OS for patients with high (above median) Texstem was significantly longer than those with low Texstem (9.9 vs 3.4 months, HR 0.398, p = 0.020). In addition, the ratio of Texstem to Texterm also showed a positive association with OS. Similarly, in mesothelioma patients, a greater percentage of Texstem was associated with longer OS in multivariate analysis (p = 0.049). The median OS for patients with high vs low Texstem was 33.5 vs 11.1 months (HR 0.302, 95% CI 0.129 – 0.705, p = 0.006). In addition, there was also a positive association between Texstem to Texterm ratio and OS. Conversely, Texterm CD8+ T cells did not impact OS in either cancer type. Conclusions: NSCLC and mesothelioma patients with greater abundance of pleural effusion stem-like exhausted CD8+ T cells exhibit better survival outcomes irrespective of patient and disease characteristics, supporting its role as a prognostic biomarker.[Table: see text]