RESUMO
CONTEXT: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. CASE REPORT: A 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure. CONCLUSION: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage.
Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Encefálicas/metabolismo , Neoplasias Colorretais/metabolismo , Hidrocortisona/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismoRESUMO
In order to provide specificity for T cell responses against pathogens and tumours, major histocompatibility complex (MHC) class I molecules present high-affinity peptides at the cell surface to T cells. A key player for peptide loading is the MHC class I-dedicated chaperone tapasin. Recently we discovered a second MHC class I-dedicated chaperone, the tapasin-related protein TAPBPR. Here, we review the major steps in the MHC class I pathway and the TAPBPR data. We discuss the potential function of TAPBPR in the MHC class I pathway and the involvement of this previously uncharacterised protein in human health and disease.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoglobulinas/imunologia , Proteínas de Membrana/imunologia , Proteínas de Membrana Transportadoras/imunologia , Sequência de Aminoácidos , Apresentação de Antígeno , Células Apresentadoras de Antígenos/citologia , Membrana Celular/química , Membrana Celular/imunologia , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunoglobulinas/genética , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Modelos Moleculares , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/genética , Peptídeos/imunologia , Transporte Proteico , Transdução de SinaisRESUMO
Despite extensive research, it remains unclear why a small proportion of HLA- B27(+) individuals develop spondyloarthropathies (SpA). Because the function of HLA-B27, as a major histocompatibility complex (MHC) class I molecule, is peptide presentation to CD8(+) T cells, research has concentrated on the role of HLA-B27 as a restriction element for CD8(+) cytotoxic T lymphocytes in pathogenesis. However, findings in the B27-transgenic animal models, together with the identification of unusual processing and presentation features of HLA-B27, have raised alternative hypotheses for the pathogenic role of HLA-B27. One such hypothesis is that HLA-B27 can be recognized by CD4(+) T lymphocytes. Here we report the identification of such unusual cells, which break the conventional rules of MHC restriction, and propose a model for the role of such CD4(+) T cells in SpA.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígeno HLA-B27/imunologia , Espondiloartropatias/imunologia , Animais , Modelos Animais de Doenças , Humanos , Relação Estrutura-AtividadeRESUMO
HLA-B27 transgenic animal models suggest a role for CD4(+) T lymphocytes in the pathogenesis of the spondyloarthropathies, and murine studies have raised the possibility that unusual forms of B27 may be involved in disease. We demonstrate that CD4(+) T cells capable of recognizing B27 can be isolated from humans by coculture with the MHC class II-negative cell line T2 transfected with B27. These CD4(+) T cells recognize a panel of B27-transfected cell lines that are defective in Ag-processing pathways, but not the nontransfected parental cell lines, in a CD4-dependent fashion. Inhibition of responses by the MHC class I-specific mAb w6/32 and the B27 binding mAb ME1 implicates the recognition of a form of B27 recognized by both of these Abs. We suggest that B27-reactive CD4(+) T cells may be pathogenic in spondyloarthropathies, particularly if factors such as infection influence expression of abnormal forms of B27.