Journal Article

MHC class-I downregulation in PD-1/PD-L1 inhibitor refractory Merkel cell carcinoma and its potential reversal by histone deacetylase inhibition: a case series

Wohlfarth, Jonas, Becker, Jürgen C, Ugurel, Selma, Drusio, Christina, Cherouny, Angela, Zimmer, Lisa, Spassova, Ivelina, Melior, Anita, Ritter, Cathrin, Schadendorf, Dirk, Sucker, Antje

2019

Overview

BackgroundMerkel cell carcinoma (MCC) is an aggressive skin cancer in which PD-1/PD-L1 blockade has shown remarkable response rates. However, a significant proportion of patients shows primary or secondary resistance against PD-1/PD-L1 inhibition, with HLA class-I downregulation and insufficient influx of CD8+ T cells into the tumor as possible immune escape mechanisms. Histone deacetylase inhibitors (HDACi) have been demonstrated to reverse low HLA class-I expression caused by epigenetic downregulation of the antigen machinery (APM) in vitro and in pre-clinical models in vivo.Case presentationsWe report four cases of patients with metastatic MCC who did not respond to immunotherapy by PD-1/PD-L1 blockade. Two of the patients received, subsequently, the HDACi panobinostat in combination with PD-1/PD-L1 blockade. Tumor biopsies of the patients were analyzed for cellular and molecular markers of antigen processing and presentation as well as the degree of T-cell infiltration.Results and conclusionLow expression of APM-related genes associated with low HLA class-I surface expression was observed in all MCC patients, progressing on PD-1/PD-L1 blockade. In one evaluable patient, of the two treated with the combination therapy of the HDACi, panobinostat and PD-1/PD-L1 blockade, reintroduction of HLA class-I-related genes, enhanced HLA class-I surface expression, and elevated CD8+ T-cell infiltration into the MCC tumor tissue were observed; however, these changes did not translate into a clinical benefit. Our findings suggest that HDACi may be useful to overcome HLA class-I downregulation as a resistance mechanism against anti-PD-1/PD-L1 antibodies in MCC patients. Prospective clinical trials are needed to evaluate this notion.

• Publisher: Springer Nature B.V
• Subject: Antigen presentation / Antigen processing / Antigens / Biopsy / Carcinoma / CD8 antigen / Clinical trials / Down-regulation / Epigenetics / Histocompatibility antigen HLA / Histone deacetylase / Immunotherapy / Infiltration / Lymphocytes T / Major histocompatibility complex / Metastases / PD-1 protein / PD-L1 protein / Skin cancer / Tumors