Abstract
Introduction: We compared the secretome of metastatic (non-small cell lung cancer (NSCLC)) and primary (mesothelioma) malignant pleural effusions, benign effusions and the published plasma profile of patients receiving chimeric antigen receptor T cells (CAR-T), to determine factors unique to neoplasia in pleural effusion (PE) and those accompanying an efficacious peripheral anti-tumor immune response.Materials and Methods: Cryopreserved cell-free PE fluid from 101 NSCLC patients, 8 mesothelioma and 13 with benign PE was assayed for a panel of 40 cytokines/chemokines using the Luminex system.Results: Profiles of benign and malignant PE were dominated by high concentrations of sIL-6Rα, CCL2/MCP1, CXCL10/IP10, IL-6, TGFβ1, CCL22/MDC, CXCL8/IL-8 and IL-10. Malignant PE contained significantly higher (p < 0.01, Bonferroni-corrected) concentrations of MIP1β, CCL22/MDC, CX3CL1/fractalkine, IFNα2, IFNγ, VEGF, IL-1α and FGF2. When grouped by function, mesothelioma PE had lower effector cytokines than NSCLC PE. Comparing NSCLC PE and published plasma levels of CAR-T recipients, both were dominated by sIL-6Rα and IL-6 but NSCLC PE had more VEGF, FGF2 and TNFα, and less IL-2, IL-4, IL-13, IL-15, MIP1α and IFNγ.Conclusions: An immunosuppressive, wound-healing environment characterizes both benign and malignant PE. A dampened effector response (IFNα2, IFNγ, MIP1α, TNFα and TNFβ) was detected in NSCLC PE, but not mesothelioma or benign PE. The data indicate that immune effectors are present in NSCLC PE and suggest that the IL-6/sIL-6Rα axis is a central driver of the immunosuppressive, tumor-supportive pleural environment. A combination localized antibody-based immunotherapy with or without cellular therapy may be justified in this uniformly fatal condition.
Highlights
We compared the secretome of metastatic (non-small cell lung cancer (NSCLC)) and primary malignant pleural effusions, benign effusions and the published plasma profile of patients receiving chimeric antigen receptor T cells (CAR-T), to determine factors unique to neoplasia in pleural effusion (PE) and those accompanying an efficacious peripheral anti-tumor immune response
There were no significant differences in single cytokine levels between NSCLC and mesothelioma samples (Figure 1, Student’s t-test, Bonferroni corrected for multiple comparisons), or between heart failure and asbestosis samples
The concentrations of 9 cytokines were significantly higher in malignant PE compared to benign (Supplementary Table 1)
Summary
We compared the secretome of metastatic (non-small cell lung cancer (NSCLC)) and primary (mesothelioma) malignant pleural effusions, benign effusions and the published plasma profile of patients receiving chimeric antigen receptor T cells (CAR-T), to determine factors unique to neoplasia in pleural effusion (PE) and those accompanying an efficacious peripheral anti-tumor immune response. The pleura represent a common site of metastasis for non-small cell lung cancer (NSCLC) and are the primary site of tumorigenesis in malignant mesothelioma These conditions are accompanied by the development of pleural effusions, accumulations of serous fluid rich in tumor cells, mesothelial cells, immune cells, and the cytokines and chemokines which they secrete. Pleural effusions are not limited to malignancies and can occur when the regulation of pleural fluid volume is disrupted by pathologic changes affecting the mechanical movement of the thoracic cage, the pulmonary or systemic circulations or lymphatic drainage [5] Benign effusions, such as those accompanying congestive heart failure or asbestosis, provide an informative contrast to malignant effusions and may reveal both the factors conditioning a site for metastasis or tumorigenesis, and differences in the pleural secretome specific to malignancy or secreted by tumor cells themselves. In this report we compare levels of 40 cytokines and chemokines (hereafter referred to as cytokines) in non-small cell lung cancer (NSCLC), mesothelioma and benign pleural effusions, with the goal of identifying druggable targets and interventions that can change the pleural environment from one that suppresses immunity and promotes tumor invasiveness, to one conducive to anti-tumor effector responses [6]
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