ABSTRACT
Immune checkpoint blockers improve the overall survival of a limited number of patients among different cancers. Identifying pathways that influence the immunological and clinical response to treatment is critical to improve the therapeutic efficacy and predict clinical responses. Recently, a key role has been assigned to innate immune mechanisms in checkpoint blockade-driven anti-tumor responses. However, inflammatory pathways can both improve and impair anti-tumor immunity. In this review, we discuss how different inflammatory pathways, particularly inflammasome activation, can influence the clinical outcome of immune checkpoint blockers. Inflammasome activation may reinforce anti-tumor immunity by boosting CD8+ T cell priming as well as by enhancing T helper type 17 (Th17) responses. In particular, we focus on the modulation of the cation channel transmembrane protein 176B (TMEM176B) and the ectonucleotidase CD39 as potential targets to unleash inflammasome activation leading to reinforced anti-tumor immunity and improved efficacy of immune checkpoint blockers. Future studies should be aimed at investigating the mechanisms and cell subsets involved in inflammasome-driven anti-tumor responses.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Apyrase , Inflammasomes/immunology , Membrane Proteins , Neoplasm Proteins , Neoplasms , Animals , Apyrase/antagonists & inhibitors , Apyrase/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Humans , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/immunology , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/immunology , Neoplasms/drug therapy , Neoplasms/immunology , Neoplasms/pathology , Th17 Cells/immunology , Th17 Cells/pathologyABSTRACT
INTRODUCTION: Tumour burden is a prognostic biomarker in metastatic melanoma. However, tumour burden is difficult to measure and there are currently no reliable surrogate biomarkers to easily and reliably determine it. The aim of this study was to assess the potential of plasma total cell free DNA as biomarker of tumour burden and prognosis in metastatic melanoma patients. MATERIALS AND METHODS: A prospective biomarker cohort study for total plasma circulating cell-free DNA (cfDNA) concentration was performed in 43 metastatic melanoma patients. For 38 patients, paired blood collections and scan assessments were available before treatment and at first response evaluation. Tumour burden was calculated as the sum of volumes from three-dimensional radiological measurements of all metastatic lesions in individual patients. RESULTS: Baseline cfDNA concentration correlated with pre-treatment tumour burden (ρ = 0.52, P < 0.001). Baseline cfDNA levels correlated significantly with hazard of death and overall survival, and a cut off value of 89 pg/µl identified two distinct prognostic groups (HR = 2.22 for high cfDNA, P = 0.004). Patients with cfDNA ≥89 pg/µl had shorter OS (10.0 versus 22.7 months, P = 0.009; HR = 2.22 for high cfDNA, P = 0.004) and the significance was maintained when compared with lactic dehydrogenase (LDH) in a multivariate analysis. We also found a correlation between the changes of cfDNA and treatment-related changes in tumour burden (ρ = 0.49, P = 0.002). In addition, the ratio between baseline cfDNA and tumour burden was prognostic (HR = 2.7 for cfDNA/tumour volume ≥8 pg/(µl*cm3), P = 0.024). CONCLUSIONS: We have demonstrated that cfDNA is a surrogate marker of tumour burden in metastatic melanoma patients, and that it is prognostic for overall survival.
Subject(s)
Biomarkers, Tumor/genetics , Cell-Free Nucleic Acids/genetics , Melanoma/genetics , Tumor Burden/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Cell-Free Nucleic Acids/blood , Female , Humans , Kaplan-Meier Estimate , Male , Melanoma/blood , Melanoma/pathology , Middle Aged , Neoplasm Metastasis , Prognosis , Prospective Studies , Young AdultABSTRACT
BACKGROUND: The application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment. PATIENTS AND METHODS: We used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy. RESULTS: Despite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel. CONCLUSION: We show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.
Subject(s)
Cell-Free Nucleic Acids/genetics , Melanoma/drug therapy , Proto-Oncogene Proteins c-kit/genetics , Vaginal Neoplasms/drug therapy , Adult , Aged , Biomarkers, Pharmacological , Carboplatin/administration & dosage , Cell-Free Nucleic Acids/drug effects , DNA, Neoplasm/drug effects , DNA, Neoplasm/genetics , Female , High-Throughput Nucleotide Sequencing , Humans , Imatinib Mesylate/administration & dosage , Melanoma/genetics , Melanoma/pathology , Middle Aged , Mutation , Paclitaxel/administration & dosage , Precision Medicine , Vaginal Neoplasms/genetics , Vaginal Neoplasms/pathology , Exome SequencingABSTRACT
La invasión de vasos linfáticos en nevos es un hecho poco comunicado. Revisamos 200 nevos de células névicas correspondientes a los últimos dos años con el objeto de buscar este fenómeno. Pudimos observarlo en dos nevos celulares compuestos, uno de ellos con rasgos congénitos, donde estaban presentes en capilares linfáticos. Existen casos comunicados de presencia de grupos de células névicas en ganglios linfáticos. Debe destacarse que la presencia de dichas células en el interior de linfáticos no debe ser considerada como índice de malignidad, como sostienen los principios de la patología clásica, y sugerimos su búsqueda para tener mayor idea de su exacta magnitud y significado (AU)
Subject(s)
Adult , Humans , Male , Female , Nevus, Pigmented/pathologyABSTRACT
La invasión de vasos linfáticos en nevos es un hecho poco comunicado. Revisamos 200 nevos de células névicas correspondientes a los últimos dos años con el objeto de buscar este fenómeno. Pudimos observarlo en dos nevos celulares compuestos, uno de ellos con rasgos congénitos, donde estaban presentes en capilares linfáticos. Existen casos comunicados de presencia de grupos de células névicas en ganglios linfáticos. Debe destacarse que la presencia de dichas células en el interior de linfáticos no debe ser considerada como índice de malignidad, como sostienen los principios de la patología clásica, y sugerimos su búsqueda para tener mayor idea de su exacta magnitud y significado
