Investigators at the Moffitt Cancer Center have released results from a multiomics research effort using a rare cohort of 56 subjects. The researchers have discovered a number of genomic alterations and oncogenic programs in patients with cutaneous T-cell lymphoma (CTCL). The team believes its research has uncovered potential therapeutic targets of this incurable, rare cancer of skin-homing T cells that is highly disfiguring and lethal at advanced stages.
“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.
The research, conducted in collaboration with scientists at MD Anderson Cancer Center and published in Cancer Research, a journal of the AACR, breaks new ground because the rarity of CTCL has made it difficult to gather adequate tissue specimens to investigate the tumor microenvironment at large cell transformation.
For their research, the team was able to study the tumor ecosystem using a multiomic approach that included whole-exome sequencing, single-cell RNAseq and immune profiling by single-cell V(D)J sequencing and multiplex immunofluorescence studies. The findings show that CTCL is characterized by high high tumor mutation burden and UV mutation signatures that are prognostic for survival.
The data also showed that transformed CTCL samples from Black patients showed significantly lower contribution of UV signatures and enrichment of mutation signatures that are associated with defective DNA mismatch repair. This is an important finding as racial disparity from CTCL are well-documented. Black patients typically show worse outcomes, and this new information may provide insights into potential genomic correlate of this disparity, which may suggest future larger studies examining predictive biomarkers of this vulnerable population.
In addition, the investigators 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. This revealed the possibility of exploiting 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. The team validated these signatures via 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.