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
The integration of genetic information in the cellular and nuclear environments is crucial for deciphering the way in which the genome functions under different physiological conditions. Experimental techniques of 3D nuclear mapping, a high-flow approach such as transcriptomic data analyses, and statistical methods for the development of co-expressed gene networks, can be combined to develop an integrated approach for depicting the regulation of gene expression. Our work focused more specifically on the mechanisms involved in the transcriptional regulation of genes expressed in muscle during late foetal development in pig. The data generated by a transcriptomic analysis carried out on muscle of foetuses from two extreme genetic lines for birth mortality are used to construct networks of differentially expressed and co-regulated genes. We developed an innovative co-expression networking approach coupling, by means of an iterative process, a new statistical method for graph inference with data of gene spatial co-localization (3D DNA FISH) to construct a robust network grouping co-expressed genes. This enabled us to highlight relevant biological processes related to foetal muscle maturity and to discover unexpected gene associations between IGF2, MYH3 and DLK1/MEG3 in the nuclear space, genes that are up-regulated at this stage of muscle development.