Defining the Clonal Evolution of Cutaneous T Cell Lymphoma
Dr. Neha Mehta-Shah
Dr. Mehta-Shah’s team has been studying the role of the immune microenvironment in Cutaneous T Cell Lymphoma (CTCL), which provided further support for the Phase I clinical trial of combined immunotherapy. The team proposed to use (1) scRNAseq and (2) exome + whole-genome sequencing to identify subclonal populations in patient-matched CTCL specimens. These were collected at multiple time points to identify pathways that contribute to disease progression and to articulate clonal evolution in this rare disease. An additional MGI collaborative proposal with Dr. Obi and Dr. Malachi Griffith included to (3) map the T-cell receptor (TCR) repertoire of clonal T cell populations to identify changes associated with progression. The integration of these data was predicted to discover progression-associated mutations and reveal profiles predictive of disease progression. This was performed via the GTAC@MGI using standard 10X TCR-seq with analysis performed by the Payton lab.
Using scRNA-plus TCR-seq on serial peripheral blood samples (16) from 6 CTCL patients, there was the identification of distinct TCR clonotypes for each patient, enabling tracking of the malignant cells for gene expression analyses at the single-cell level. The scRNAseq revealed a Th2 or Treg phenotype immune cell phenotype in the CTCL cells from the advanced cases. The Treg profile included expression of FOXP3 and other Treg markers. In the same advanced tumors, we identified the deletion of DNMT3A, a DNA methyltransferase known to suppress the expression of FOXP3. These data suggest that DNMT3A loss and consequent epigenetic alterations may be a previously unrecognized link between lymphoma and tumor-mediated immune suppression in CTCL.
Future research includes moving forward with these findings and others from related studies in the Payton lab to elucidate how these changes contribute to CTCL progression. In addition, Dr. Mehta-Shah is beginning an investigator-initiated clinical trial of immunotherapy in CTCL which will enable them to evaluate the role of the pathways identified in patients before, during, and after immunotherapy. In addition, this project was invited to be part of the LEAP innovation program.
For continued educational resources by this team, read the publication:
Andrews Jared M., Schmidt Jennifer A., Carson Kenneth R., Musiek Amy C., Mehta-Shah Neha, Payton Jacqueline E. Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma. EBioMedicine. 2019 Aug; 46:170-183. doi 10.1016/j.ebiom.2019.07.053 Epub 2019 Jul26. PubMed PMID: 31358475.