Damotte, D. | Search bioRxiv

bioRxiv2021

Disentangling heterogeneity of Malignant Pleural Mesothelioma through deep integrative omics analyses

Malignant Pleural Mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Using the largest series of whole-genome sequencing data integrated with transcriptomic and epigenomic data using multi-omic factor analysis, we demonstrate that MPM heterogeneity arises from four sources of variation: tumor cell morphology, ploidy, adaptive immune response, and CpG island methylator phenotype. Previous genomic studies focused on describing only the tumor cell morphology factor, although we robustly find the three other sources in all publicly available cohorts. We prove how these sources of variation explain the biological functions performed by the cancer cells, and how genomic events shape MPM molecular profiles. We show how these new sources of variation help understand the heterogeneity of the clinical behavior of MPM and drug responses measured in cell lines. These findings unearth the interplay between MPM functional biology and its genomic history, and ultimately, inform classification, prognostication and treatment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/461908v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@b6c43corg.highwire.dtl.DTLVardef@10d45a9org.highwire.dtl.DTLVardef@58746eorg.highwire.dtl.DTLVardef@143f880_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

CAR T cell entry into tumor islets is a two-step process dependent on IFNγ and ICAM-1

Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown remarkable clinical efficacy against advanced B cell malignancies but not yet against solid tumors. Here, we used fluorescent imaging microscopy and ex vivo assays to compare the early functional responses (migration, Ca2+ and cytotoxicity) of CD20 and EGFR CAR T cells upon contact with malignant B and carcinoma cells. Our results indicate that CD20 CAR T cells rapidly form productive ICAM-1-dependent conjugates with their targets. By comparison, EGFR CAR T cells only interact at first with a subset of carcinoma cells located at the periphery of tumor islets. After this initial peripheral activation, EGFR CAR T cells progressively infiltrate the center of tumor cell regions. The analysis of this two-step entry process shows that activated CAR T cells trigger the upregulation of ICAM-1 on tumor cells in an IFN{gamma}-dependent pathway. The blockade of ICAM-1/LFA-1 interactions prevents CAR T cell recruitment into tumor islets. The requirement for IFN{gamma} and ICAM-1 to enable CAR T cell entry into tumor islets is of significance for improving CAR T strategy in solid tumors.

immunology↗