Pleural Fluid Has Pro-Growth Biological Properties Which Enable Cancer Cell Proliferation.

OBJECTIVES: Patients with malignant pleural mesothelioma (MPM) or pleural metastases often present with malignant pleural effusion (MPE). This study aimed to analyze the effect of pleural fluid on cancer cells. MATERIALS AND METHODS: Established patient-derived cancer cell cultures derived from MPE (MPM, breast carcinoma, lung adenocarcinoma) were seeded in 100% pleural fluid (exudate MPM MPE, transudate MPE, non-MPE transudate fluid) and proliferation was monitored. In addition, the establishment of new MPM cell cultures, derived from MPE specimens, was attempted by seeding the cells in 100% MPE fluid. RESULTS: All established cancer cell cultures proliferated with similar growth rates in the different types of pleural fluid. Primary MPM cell culture success was similar with MPE fluid as with full culture medium. CONCLUSIONS: Pleural fluid alone is adequate for cancer cell proliferation in vitro, regardless of the source of pleural fluid. These results support the hypothesis that pleural fluid has important pro-growth biological properties, but the mechanisms for this effect are unclear and likely not malignant effusion specific.

Human cancer germline antigen-specific cytotoxic T cell-what can we learn from patient.

In this review, we will highlight the importance of cancer germline antigen-specific cytotoxic CD8+ T lymphocytes (CTL) and the factors affecting antitumor CTL responses. In light of cancer immunotherapy, we will emphasis the need to further understand the features, characteristics, and actions of modulatory receptors of human cancer germline-specific CTLs, in order to determine the optimal conditions for antitumor CTL responses.

Defective Interferon Gamma Production by Tumor-Specific CD8+ T Cells Is Associated With 5'Methylcytosine-Guanine Hypermethylation of Interferon Gamma Promoter.

Interferon gamma (IFNγ) supports effector responses of CD8+ cytotoxic T lymphocytes (CTLs) and is a surrogate marker for detection of antigen-specific T cells. Here, we show that tumor-specific CTL clones have impaired IFNγ expression and production upon activation. Assessment of the relationship between IFNγ production and the 5'methylcytosine-guanine (CpG) dinucleotide methylation of the IFNγ promoter using bisulfite treatment has shown that IFNγ- CTL clones accumulates CpG hypermethylation within the promoter at key transcription factor binding sites (-186 and -54), known to be vital for transcription. We confirmed these findings using ex vivo isolated and short-term expanded bulk tumor-specific CTL lines from four cancer patients and demonstrated that IFNγ methylation inversely correlates with transcription, protein level, and cytotoxicity. Altogether, we propose that a sizeable portion of human tumor-specific CTLs are deficient in IFNγ response, contributed by CpG hypermethylation of the IFNγ promoter. Our findings have important implications for immunotherapy strategies and for methods to detect human antigen-specific T cells.

Clinical perspective and practices on pleural effusions in chronic systemic inflammatory diseases.

Systemic inflammatory diseases are a heterogeneous family of autoimmune chronic inflammatory disorders that affect multiple systems within the human body. Connective tissue disease (CTD) is a large group within this family characterised by immune-mediated inflammation of the connective tissue. This group of disorders are often associated with pleural manifestations. CTD-induced pleuritis exhibits a wide variety of symptoms and signs including exudative pleural effusions and chest pain. Accurate estimation of prevalence for CTD-related pleuritis is challenging as small effusions are asymptomatic and remain undetected. Rheumatoid arthritis and systemic lupus erythematosus are frequent CTDs and present with pleural pathology in approximately 5-20% and 17-60% of cases, respectively. By contrast, pleural involvement in systemic sclerosis, eosinophilia-myalgia syndrome, mixed connective tissue disease, ankylosing spondylitis, polymyositis and dermatomyositis syndrome is rare. Clinical management depends on the severity of symptoms; however, most effusions resolve spontaneously. In this review we discuss the pathophysiological mechanisms and the clinical considerations of CTD-induced pleuritis.

Self-Maintaining CD103+ Cancer-Specific T Cells Are Highly Energetic with Rapid Cytotoxic and Effector Responses.

Enrichment of CD103+ tumor-infiltrating T lymphocytes (TIL) is associated with improved outcomes in patients. However, the characteristics of human CD103+ cytotoxic CD8+ T cells (CTL) and their role in tumor control remain unclear. We investigated the features and antitumor mechanisms of CD103+ CTLs by assessing T-cell receptor (TCR)-matched CD103+ and CD103- cancer-specific CTL immunity in vitro and its immunophenotype ex vivo Interestingly, we found that differentiated CD103+ cancer-specific CTLs expressed the active form of TGFß1 to continually self-regulate CD103 expression, without relying on external TGFß1-producing cells. The presence of CD103 on CTLs improved TCR antigen sensitivity, which enabled faster cancer recognition and rapid antitumor cytotoxicity. These CD103+ CTLs had elevated energetic potential and faster migration capacity. However, they had increased inhibitory receptor coexpression and elevated T-cell apoptosis following prolonged cancer exposure. Our data provide fundamental insights into the properties of matured human CD103+ cancer-specific CTLs, which could have important implications for future designs of tissue-localized cancer immunotherapy strategies.

Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8+ Tumor-Infiltrating T Lymphocyte Responses.

Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141+ conventional dendritic cells (cDC) contributed to HLA-E enrichment in carcinomas. Different cancer types showed a similar pattern of enrichment. Enrichment correlated to NKG2A upregulation on CD8+ tumor-infiltrating T lymphocytes (TIL) but not on CD4+ TILs. CD94/NKG2A is exclusively expressed on PD-1high TILs while lacking intratumoral CD103 expression. We also found that the presence of CD94/NKG2A on human tumor-specific T cells impairs IL2 receptor-dependent proliferation, which affects IFNγ-mediated responses and antitumor cytotoxicity. These functionalities recover following antibody-mediated blockade in vitro and ex vivo Our results suggest that enriched HLA-E:CD94/NKG2A inhibitory interaction can impair survival of PD-1high TILs in the tumor microenvironment.