RESUMO
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy for which novel therapeutics with improved efficacy are greatly needed. To provide support for clinical immune checkpoint blockade, we comprehensively evaluated the expression of therapeutically targetable immune checkpoint molecules on primary MCL cells. MCL cells showed constitutive expression of Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1), variable CD200, absent PD-L2, Lymphocyte Activation Gene 3 (LAG-3), and Cytotoxic T-cell Associated Protein 4 (CTLA-4). Effector cells from MCL patients expressed PD-1. Co-culture of MCL cells with T-cells induced PD-L1 surface expression, a phenomenon regulated by IFNγ and CD40:CD40L interaction. Induction of PD-L1 was attenuated by concurrent treatment with ibrutinib or duvelisib, suggesting BTK and PI3K are important mediators of PD-L1 expression. Overall, our data provide further insight into the expression of checkpoint molecules in MCL and support the use of PD-L1 blocking antibodies in MCL patients.
Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Linfoma de Célula do Manto/genética , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Humanos , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcrição GênicaAssuntos
Resistencia a Medicamentos Antineoplásicos , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Humanos , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologiaRESUMO
BACKGROUND: Basal cell carcinoma (BCC) tumors are the most common skin cancer and are highly immunogenic. OBJECTIVE: The goal of this study was to assess how immune-cell related gene expression in an initial BCC tumor biopsy was related to the appearance of subsequent BCC tumors. MATERIALS AND METHODS: Levels of mRNA for CD3ε (a T-cell receptor marker), CD25 (the alpha chain of the interleukin (IL)-2 receptor expressed on activated T-cells and B-cells), CD68 (a marker for monocytes/macrophages), the cell surface glycoprotein intercellular adhesion molecule-1 (ICAM-1), the cytokine interferon-γ (IFN-γ) and the anti-inflammatory cytokine IL-10 were measured in BCC tumor biopsies from 138 patients using real-time PCR. RESULTS: The median follow-up was 26.6 months, and 61% of subjects were free of new BCCs two years post-initial biopsy. Patients with low CD3ε CD25, CD68, and ICAM-1 mRNA levels had significantly shorter times before new tumors were detected (pâ=â0.03, pâ=â0.02, pâ=â0.003, and pâ=â0.08, respectively). Furthermore, older age diminished the association of mRNA levels with the appearance of subsequent tumors. CONCLUSIONS: Our results show that levels of CD3ε, CD25, CD68, and ICAM-1 mRNA in BCC biopsies may predict risk for new BCC tumors.
