RESUMEN
Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.
Asunto(s)
Carcinoma de Células de Merkel/terapia , Genes MHC Clase I/genética , Inmunoterapia Adoptiva/métodos , Recurrencia Local de Neoplasia/genética , Infecciones por Polyomavirus/terapia , Neoplasias Cutáneas/terapia , Escape del Tumor/genética , Infecciones Tumorales por Virus/terapia , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/virología , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Genes MHC Clase I/inmunología , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/trasplante , Masculino , Poliomavirus de Células de Merkel/inmunología , Poliomavirus de Células de Merkel/aislamiento & purificación , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Infecciones por Polyomavirus/genética , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/virología , Neoplasias Testiculares/inmunología , Neoplasias Testiculares/secundario , Neoplasias Testiculares/virología , Transcripción Genética/inmunología , Trasplante Autólogo/métodos , Infecciones Tumorales por Virus/genética , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virologíaRESUMEN
Seeking biomarkers reflecting disease development in cystic echinococcosis (CE), we used a proteomic approach linked to immunological characterisation for the identification of respective antigens. Two-dimensional gel electrophoresis (2-DE) of sheep hydatid fluid, followed by immunoblot analysis (IB) with sera from patients with distinct phases of disease, enabled us to identify by mass spectrometry heat shock protein 20 (HSP20) as a potential marker of active CE. Using IB, antibodies specific to the 34 kDa band of HSP20 were detected in sera from 61/95 (64%) patients with CE, but not in sera from healthy subjects. IB revealed anti-HSP20 antibodies in a higher percentage of sera from patients with active disease than in sera from patients with inactive disease (81 vs. 24%; P = 10(-4)). These primary results were confirmed in a long-term follow-up study after pharmacological and surgical treatment. Herewith anti-HSP20 antibody levels significantly decreased over the course of treatment in sera from patients with cured disease, relative to sera from patients with progressive disease (P = 0·017). Thus, during CE, a comprehensive strategy of proteomic identification combined with immunological validation represents a promising approach for the identification of biomarkers useful for the prognostic assessment of treatment of CE patients.