Key genomic alterations and potential therapeutic vulnerabilities in transformed cutaneous T-cell lymphoma
The discoveries from this multiomics study could drive new therapies for
this rare cancer
Date:
February 28, 2022
Source:
H. Lee Moffitt Cancer Center & Research Institute
Summary:
Researchers have shared a comprehensive multiomics study from a
rare cohort of 56 patients with transformed CTCL and identified
several genomic alterations and oncogenic programs that may be
potential novel therapeutic targets.
FULL STORY ========================================================================== Cutaneous T-cell lymphoma (CTCL) is an incurable, rare cancer of
skin-homing T cells that is highly disfiguring and lethal at advanced
stages. The most common form of CTCL, mycosis fungoides, is characterized
by a cutaneous patch, plaque and/or tumor lesions. Another form, Sezary syndrome, is the leukemic variant of CTCL with circulating malignant
T cells in the blood. Large cell transformation occurs in a subset of
mycosis fungoides and Sezary patients heralding immediate transition
to an aggressive large cell lymphoma. However, given the rare nature
of CTCL, gathering adequate tissue specimens to investigate the tumor microenvironment at large cell transformation has been a significant
roadblock to potential therapeutic advances.
==========================================================================
In a new article published in Cancer Discovery, a journal of the American Association for Cancer Research, Moffitt Cancer Center researchers shared
a comprehensive multiomics study from a rare cohort of 56 patients with transformed CTCL and identified several genomic alterations and oncogenic programs that may be potential novel therapeutic targets.
"While cancer death rates have significantly declined for many common
cancers in the past decade, there is a sobering underrepresentation
of this success in rare cancers, such as CTCL, particularly in the
vulnerable racial minority groups," said study senior author Pei-Ling
Chen, M.D., Ph.D., associate member of the Pathology and Cutaneous
Oncology Departments and member of the Moffitt Cutaneous Lymphoma Multidisciplinary Clinic, one of the largest CTCL referral centers in
the U.S.
Moffitt researchers, in collaboration with scientists at MD Anderson
Cancer Center, performed multiomics profiling of 70 biopsies and 16 fresh tissue specimens from patients with transformed CTCL and investigated
the tumor ecosystem using integrative approaches spanning whole exome sequencing, single- cell RNAseq and immune profiling by single-cell V(D)J sequencing and multiplex immunofluorescence studies. The researchers
discovered that the genomic landscape of transformed CTCL is characterized
by a high tumor mutation burden and UV mutation signatures that are
prognostic for survival. Importantly, transformed CTCL samples from Black/African American patients showed significantly lower contribution of
UV signatures and enrichment of mutation signatures that are associated
with defective DNA mismatch repair. The research team also identified
several recurrently mutated pathways and exome-based driver events in transformed CTCL and showed dissimilarity in the genomic landscape of transformed T cells in skin versus leukemic T cells in blood, revealing opportunities to exploit differential or synergistic therapeutic vulnerabilities in the two body compartments at advanced stage disease.
To interrogate the transformed CTCL tumor ecosystem at single-cell
resolution, the researchers then profiled 34,912 cells from 16 fresh
tissue biopsies by single-cell RNA and V(D)J sequencing. The research
team identified the core oncogenic programs that malignant T cells
exploit at large cell transformation, including metabolic reprogramming
toward oxidative phosphorylation, cellular plasticity, upregulation
of MYC, E2F and macrophage migration inhibitory factor activities, and downregulation of MHC-I suggestive of immune surveillance escape. These signatures were further validated by pharmacologic perturbation studies
using novel small molecule inhibitors of oxidative phosphorylation and
MUC and multiplex immunofluorescence imaging.
"While further validation in larger cohorts and pre-clinical models
are needed, our investigation provides a key resource to the community
with the largest collection of transformed CTCL samples studied to date,
the first comprehensive compendium of genomic alterations at large cell transformation, a blueprint for dissecting the T-cell lymphoma tumor microenvironment at single-cell resolution and identifies potential
prognostic signatures and novel therapeutic targets in transformed
CTCL. We anticipate results from this study can be extrapolated to other
T-cell lymphomas and will help usher novel immunotherapeutic strategies
to combat this currently incurable cancer," said Chen.
While racial disparity is well-known to exist in CTCL, with Black and
African American patients showing worse clinical outcomes, potential
biological factors underlying this disparity are poorly understood. The researchers hope that their findings can provide insights into potential genomic correlate of this disparity. Future studies involving larger
sample size from the vulnerable population and research into their tumor microenvironment for predictive biomarkers and novel therapeutic targets
will hopefully help reduce racial disparity in CTCL.
This study was supported by the Moffitt Foundation, Moffitt Clinical
Science Fund, Miles for Moffitt, Total Cancer Care, the Donald A. Adam
Melanoma & Skin Cancer Center of Excellence and the National Cancer
Institute (P30-CA076292, R01CA240434).
========================================================================== Story Source: Materials provided by H._Lee_Moffitt_Cancer_Center_&_Research_Institute. Note: Content may be
edited for style and length.
========================================================================== Journal Reference:
1. Xiaofei Song et al. Genomic and single-cell landscape reveals novel
drivers and therapeutic vulnerabilities of transformed
cutaneous T-cell lymphoma. Cancer Discovery, 2022 DOI:
10.1158/2159-8290.CD-21-1207 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/02/220228114343.htm
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