1050 Single cell transcriptome and epigenome profiling reveals the diversity of T cell states inex vivogrown tumor-infiltrating lymphocytes from malignant pleural mesothelioma

Abstract

Background Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer associated with exposure to asbestos that lacks effective treatment options. 1 Immunotherapy approaches remain challenging with a current paucity of knowledge on the tumor-infiltrating lymphocyte (TIL) land-scape. 2 We aimed to generate a reference transcriptomic and epigenomic atlas of MPM T cell subpopulations that could inform on cellular features and states of propagated ex vivo cells to allow new immunotherapy design. IL9R-Tcells, five CD8-MKI67 and CD8-TOX), four gamma-delta T cell clusters (?d-TRDC), and one unique cluster (MALAT1). scATAC-seq analysis of the MPM TIL paired with their transcriptomic clusters validated the presence of existing cell states with trajectory analysis confirming the separation of the distinct cell states. Activation and inhibitory markers showed heterogenous pattern. Upregulation of activation markers OX40 ( TNFRSF4*** ) and ICOS*** was present in CD4-CD40LG and OX40 ( TNFRSF4*** ) marker in IL9R-Tcells. Moreover, CD4-CD40LG showed high upregulation of CTLA4*** and GITR ( TNFRSF18*** ), whereas, among CD8+ subsets, GITR *** expression was observed only in gd -TRDC and IL9R-Tcells. gd -TRDC also displayed heterogenous upregulation of other inhibitory markers LAG3 and TOX.