Secretome of pleural effusions associated with non-small cell lung cancer (NSCLC) and malignant mesothelioma: therapeutic implications

Our plain-English summary of Secretome of pleural effusions associated with non-small cell lung cancer (NSCLC) and malignant mesothelioma: therapeutic implications, by A.D. Donnenberg, J.D. Luketich, V.S. Donnenberg (Oncotarget, 2019).

The study

• Authors: A.D. Donnenberg, J.D. Luketich, V.S. Donnenberg
• Journal: Oncotarget
• Published: 2019;10(60):6456-6465
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study measured 40 cytokines (immune signaling proteins) in stored pleural effusion fluid, which collects around the lungs. Samples came from 101 patients with non-small cell lung cancer (NSCLC), 8 with mesothelioma, and 13 without pleural malignancy (11 heart failure, 2 asbestosis). No asbestos-exposure measurements were reported. No single cytokine differed significantly between NSCLC and mesothelioma fluid, or between heart failure and asbestosis fluid. The Results reported 9 cytokines significantly higher in malignant than benign fluid but listed 8; the Discussion also named GM-CSF (p = 0.0002). In benign fluid, IL-6 averaged 2.6 ng/mL and its soluble receptor sIL-6Rα measured 13.0 ng/mL. In most cytokine groups sorted by function, NSCLC and mesothelioma fluid were alike and both differed significantly from benign fluid. In the anti-tumor 'effector' group, NSCLC fluid was higher than benign (p = 0.00001) and mesothelioma fluid (p = 0.013); mesothelioma fluid did not differ significantly from benign (p = 0.7). The authors concluded that the IL-6/sIL-6Rα pathway may be central to an immune-suppressing pleural environment. They suggested combination therapies targeting IL-6Rα and VEGF.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory comparison of cytokine levels in stored, cell-free pleural effusion fluid from patient groups. Results were also compared with plasma data published by another study (Teachey et al.) of patients receiving CAR-T therapy.
• Who was studied: Pleural effusion samples from 101 NSCLC patients, 8 mesothelioma patients and 13 patients without pleural malignancy (11 with heart failure, 2 with asbestosis). Samples were collected under an IRB exemption or an IRB-approved protocol. Collection dates and location are not stated beyond the authors' University of Pittsburgh and UPMC affiliations.
• Exposure: No asbestos-exposure measurements, fiber types or doses were reported. The groups were defined by disease, and the benign group included asbestos exposure without malignancy (asbestosis).
• Main results:
  • No single cytokine level differed significantly between NSCLC and mesothelioma effusions.
  • No significant differences were found between heart failure and asbestosis effusions (data not shown).
  • The Results section states that 9 cytokines were significantly higher in malignant (NSCLC plus mesothelioma) effusions than in benign effusions.
  • The Discussion names GM-CSF as significantly higher in malignant than in benign effusions (Bonferroni corrected p = 0.0002).
  • In benign effusions, IL-6 had a mean of 2.6 ng/mL and sIL-6Rα measured 13.0 ng/mL.
  • In most functional cytokine groups, NSCLC and mesothelioma effusions were indistinguishable from each other and significantly different from benign effusions (p less than 0.002, Bonferroni corrected).
  • In the effector cytokine group, NSCLC effusions were higher than benign effusions (p = 0.00001) and higher than mesothelioma effusions (p = 0.013). Mesothelioma effusions were indistinguishable from benign effusions in this group (p = 0.7).
  • The authors compared NSCLC effusions with plasma values from CAR-T recipients published by another study. Against plasma from patients with no or minimal cytokine release syndrome, NSCLC effusions had lower IL-2, IL-4, IL-13, IL-15, MIP1α and IFNγ, and higher IL-6, VEGF, FGF2 and TNFα.
• The authors' conclusion: The authors concluded that the IL-6/sIL-6Rα pathway may be central to the immunosuppressive, growth-promoting, wound-healing environment of injured pleura. They suggested that combination therapies might target IL-6Rα and VEGF in addition to PD1.
• Limitations the authors state:
  • Some cytokines have several functions and could have been placed in more than one functional category.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Effusion, Non-Small Cell Lung Cancer, Mesothelioma, Cytokine, Immunotherapy.

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