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SITC 2022: Cellular Research May Lead to the Next Generation of Therapies for Myeloma

By: Joseph Fanelli
Posted: Tuesday, November 22, 2022

At the 2022 Society for Immunotherapy of Cancer (SITC) Annual Meeting (Abstract 1220), Jooeun Bae, PhD, of the Dana-Farber Cancer Institute, Boston, and colleagues shared their research on the genetic/epigenetic mechanisms and regulatory elements that may serve as important functions during the lineage-specific commitment of hematopoietic progenitor cells developed from induced pluripotent stem cells into CD8-positive cytotoxic T lymphocytes. These recognized elements may further help to craft the next generation of regenerative medicines for multiple myeloma, providing T-cell lineage commitment from progenitor cells.

In this study, the authors applied interferon-producing HLA-A2 heteroclitic B-cell maturation antigen (BCMA) 72-80–specific CD8-positive cytotoxic T lymphocytes for induced pluripotent stem cells via transduction of four reprogramming factors. After the investigators characterized the BCMA-specific induced pluripotent stem cells with high pluripotency potential, an embryoid body was formed from the induced pluripotent stem cells and further polarized into mesoderm layer development. BCMA-specific embryoid body–derived hematopoietic progenitor cells were sorted and induced to undergo T-cell differentiation in the presence of Fc-DLL4 signaling and rectonectin.

An RNA-sequencing analysis showed unique transcriptional profiles of hematopoietic progenitor cells from several induced pluripotent stem cells clones committing to CD8-positive T cells and other cell lineages. Additionally, a principal component analysis revealed a high similarity and low variability of transcription profiles within the replicates of hematopoietic progenitor cells committed to the same cell lineage. The authors also found distinct genome-wide shifts and differential gene-expression profiles in hematopoietic progenitor cells that were committed to each specific cell differentiation pathway.

Specifically, the authors noted, the hematopoietic progenitor cells committed to CD8-positive T cells employed a diverse collection of modulators that promoted the development of T-cell maturation, specific immune response regulation, memory T cells, cytotoxicity, and interferon induction. Specific repression genes were also identified in the hematopoietic progenitor cells committed to CD8-positive T cells. Those differentiated CD8-positive T cells were primarily CD45RO8-positive memory cytotoxic T lymphocytes, the authors said, and fully rejuvenated without immune checkpoint expression and regulatory T cells with high anti–multiple myeloma activity.

Disclosure: No information regarding conflicts of interest was provided.

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