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
Lesions of the medial preoptic area (MPOA) result in the robust display of steroid-induced lordosis by otherwise unresponsive, immature guinea pigs. This study was designed to test the hypothesis that destruction of this region also hastens the onset of ovarian cyclicity, and to ascertain whether lesions of the septum produce effects on puberty similar to those observed following MPOA lesions. Juvenile (13-15 days old), ovariectomized or ovary-intact guinea pigs received bilateral electrolytic or sham lesions of the MPOA or septum. Bilateral lesions of the septum did not influence the display of lordosis or any aspect of estrous cyclicity. However, a higher percentage of guinea pigs with MPOA lesions than with sham lesions displayed progesterone-facilitated lordosis at 22, 29, and 39 days of age; by 49 days of age, the two groups responded in a similar, robust fashion. Females with MPOA lesions were significantly heavier and older than sham-lesioned or nonmanipulated females on the day of first vaginal opening. These data suggest that activity in the MPOA tonically inhibits the display of progesterone-facilitated lordosis through at least 39 days of age but does not suppress the onset of ovarian cyclicity in guinea pigs. Contrary to our hypothesis and in contrast to what has been observed in rats, signals originating in or passing through the MPOA may be required in order for estrous cyclicity to be initiated at the appropriate age. Furthermore, neither of these effects of MPOA lesions appears to be due to damaging efferent or afferent projections through the septum.