Discovery of therapeutic targets in peripheral T cell lymphoma not otherwise specified (PTCL-NOS)

Abstract

Peripheral T cell lymphomas (PTCL) comprise a group of rare, heterogenous and aggressive malignancies affecting post-thymic T cells and/or Natural Killer cells, which account for 15% of all non-Hodgkin lymphomas. After diagnosis ~30% PTCL cannot be classified into a specific entity and are designated as PTCL Not Otherwise Specified (PTCL-NOS), being the commonest subtype, with a poor prognosis (50% overall survival after 3 years); in the UK, its treatment is based on chemotherapy, with common development of chemoresistance and low survival after relapse. New treatments have been attempted with limited success. The present project aimed at discovering therapeutic targets in PTCL-NOS upregulated in tumours to enable the development of antibody based immunotherapies.
First, potential antibody targets were identified from the literature (PDGFRa, ENO1, IL10R, IL13Ra1, IL4R, CXCR7, NOTCH1), followed by evaluation of mRNA and surface protein levels in 2 PTCL-NOS primary tumour samples by CITE-Seq.
A second strategy was applied, based on discovering therapeutic targets by bioinformatic analysis of 2 public PTCL-NOS gene expression datasets, where 1098 candidate genes (CG) were found upregulated in tumours compared to healthy T cell subsets. To discover tumour specific targets with minimal expression in healthy tissues, the expression of the 1098 CG was evaluated in public gene expression datasets of non malignant lymph nodes, finding 61 genes lowly expressed, of which 26 were lowly expressed at mRNA and protein across healthy human tissues (public data). Only CG expressed in >90% of PTCL-NOS patients, were considered. The 10 highest ranked CG were assessed by IHC in PTCL tumours, resulting in 4 candidate targets highly expressed in PTCL-NOS.
Moreover, the present project dissected the PTCL-NOS tumour microenvironment composition by CIBERSORT deconvolution of microarray based gene expression datasets and by CITE-Seq. In the latter, CD7-T cells were found and proposed as malignant T cells, which featured CNV gains compared to CD7+ T cells. Furthermore, by means of a gene set enrichment analysis and gene ontology of biological processes, angiogenesis and epithelial to mesenchymal transition (EMT) were highly enriched in PTCL-NOS.
The 4 discovered candidate therapeutic targets, ITGA9, CDH5 (surface proteins), ERG and FGF13 (intracellular proteins) were also involved in EMT angiogenesis, and metastasis in other malignancies. Cell type gene expression inference by CIBERSORTx, suggested that the 4 genes were mainly expressed by myeloid cells in PTCL-NOS. Future work is needed to determine the cell type expression at protein level and to elucidate the role of these candidate molecules in the PTCL-NOS context, in order to generate targeted therapies against these targets.

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Identifiers

ORCID for Sonia Gabriela Murillo Barrera: orcid.org/0009-0000-0800-8507

ORCID for Sean Lim: orcid.org/0000-0002-2768-4858

ORCID for Mark Cragg: orcid.org/0000-0003-2077-089X

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