Decreased RORC expression and downstream signaling in HTLV‐1‐associated adult T‐cell lymphoma/leukemia uncovers an antiproliferative IL17 link: A potential target for immunotherapy?

Abstract

Retinoic acid‐related drugs have shown promising pre‐clinical activity in Adult T‐cell Leukemia/Lymphoma, but RORC signaling has not been explored. Therefore, we investigated transcriptome‐wide interactions of the RORC pathway in HTLV‐1 and ATL, using our own and publicly available gene expression data for ATL and other leukemias. Gene expression data from ATL patients were analyzed using WGCNA to determine gene modules and their correlation to clinical and molecular data. Both PBMCs and CD4 + T‐Cells exhibited decreased RORC expression in four different ATL cohorts. A small subset of RORC hi ATL patients was identified with significantly lower pathognomonic CADM1 and HBZ levels but similar levels of other ATL markers (CD4/CD25/CCR4), hinting at a less aggressive ATL subtype. An age‐dependent decrease in RORC expression was found in HTLV‐1‐infected individuals, but not in healthy controls, suggesting an early molecular event predisposing to leukemogenesis. Genes upstream of RORC signaling were members of a proliferative gene module (containing proliferation markers PCNA/Ki67), whereas downstream members clustered in an anti‐proliferative gene module. IL17C transcripts showed the strongest negative correlation to PCNA in both ATL cohorts, which was replicated in two large cohorts of T‐ and B‐cell acute lymphoid leukemia (ALL). Finally, IL17C expression in purified CD4 + CCR4 + CD26‐CD7‐ “ATL‐like” cells from HTLV‐1‐infected individuals and ATL patients was negatively correlated with clonality, underscoring a possible antileukemic/antiproliferative role. In conclusion, decreased RORC expression and downstream signaling might represent an early event in ATL pathogenesis. An antiproliferative IL17C/PCNA link is shared between ATL, T‐ALL and B‐ALL, suggesting (immuno)therapeutic benefit of boosting RORC/IL17 signaling.

Identification and Verification of Tumor Immune Microenvironment-Related Prognostic Genes in Kidney Renal Clear Cell Carcinoma

“…We also found that expression of RORC was comparable in tumor and normal tissues, although its expression level was significantly lower in advanced-stage tumor tissues. RORC is a regulator of the proinflammatory Th17/interleukin-17 axis in adult T-cell leukemia [ 34 ], and low expression of RORC was a negative prognostic indicator of KIRC in our study. Thus, further studies are needed to assess the potential functions and mechanisms of RORC in immunotherapy.…”

XPO1 inhibitors represent a novel therapeutic option in Adult T-cell Leukemia, triggering p53-mediated caspase-dependent apoptosis

“…We and others have previously demonstrated that a combined in vitro, ex vivo and in silico approach might recapitulate the ATL in vivo response 16 – 19 . In addition, we have also shown that HTLV-1-transformed MT-2 and MT-4 cells phenocopy primary ATL cells 18 in their relative resistance to the antiproliferative and proapoptotic effects of IFN-α 16 , 17 .…”

The HTLV-1 viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape

“…Our molecular understanding of genomics and transcriptomics deregulation following HTLV-1 infection has come from studying ATLL patient samples [ 6 , 20 , 21 ]. Because Tax and HBZ show different expression kinetics during ATLL progression [ 22 ], it has remained challenging to systematically analyze the relative contribution of each viral protein in reprogramming the host cell’s transcriptome and proteome.…”