Biology subjects

Cha, N.

Publications and source records attributed to Cha, N..

3 recordsLinked to original sources

bioRxiv2026

HLA-A*11:01-Restricted T Cell Receptors Targeting Mutant NPM1 for Adoptive Cell Therapy in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy associated with a poor prognosis and an unmet need for more effective treatment options, particularly after relapse. One potential approach to address this need, which has been used successfully in solid tumors, is adoptive transfer of T cells engineered to express specific T cell receptors (TCRs). Particularly attractive are TCRs that can target epitopes derived from oncogenes on which cancer cells depend while sparing normal cells that do not harbor the mutation. One promising oncogenic target in AML is mutated nucleophosmin 1 (mtNPM1), present in up to 30% of AML cases. Most NPM1 mutations result in a common frameshifted sequence that generates peptides presented by several class I human leukocyte antigens (HLAs), such as HLA-A*11:01. In this study, we vaccinated HLA-A*11:01-transgenic mice with the mtNPM1 peptide AVEEVSLRK and isolated six functional TCRs from mtNPM1-reactive lymphocytes. When engineered into human T cells, two of these TCRs consistently mediated robust and specific lysis of an AML cell line and primary AML cells co-expressing HLA-A*11:01 and mtNPM1. Neither TCR recognized related human peptides, HLA-A*11:01-expressing normal peripheral blood mononuclear cells or stem/progenitor cells, or cells expressing diverse allogeneic HLAs, suggesting a low risk of cross-reactivity and alloreactivity. In an AML xenograft model, both TCRs controlled AML in hematopoietic organs, although extramedullary tumors emerged during treatment, potentially reflecting the aggressive behavior of the model that may not be representative of AML in patients. Together, these data suggest that the two TCRs represent strong candidates for further preclinical development in adoptive T cell therapy for NPM1-mutated, HLA-A*11:01-positive AML. These results also support the use of HLA-transgenic mice as a platform for generating TCRs targeting oncogene-derived epitopes in hematologic malignancies.

immunology↗

bioRxiv2026

Mitochondrial metabolic remodeling drives innate immune activation in Drosophila hemocytes

Innate immune cells rapidly reprogram their metabolism upon activation, yet the metabolic basis of this flexibility in invertebrate systems remains largely unexplored. Here, we investigate the metabolic landscape of Drosophila larval hemocytes, functional analogs of vertebrate myeloid cells, across developmental stages, genotypes, and immune activation states, by combining metabolic flux measurements with single-cell transcriptomics. Under homeostatic conditions, hemocytes rely predominantly on mitochondrial oxidative phosphorylation for ATP production, with minimal glycolytic contribution. Immune activation, particularly lamellocyte differentiation, drives enhanced mitochondrial respiration and metabolic flexibility, accompanied by structural remodeling of the mitochondrial network. Mechanistically, functional lamellocytes require Drp1-mediated mitochondrial fission and utilize glucose and trehalose as primary carbon sources to sustain mitochondrial respiration, which is essential for effective immune responses. Overall, these findings establish that mitochondrial metabolic reprogramming is a conserved feature of innate immune activation in myeloid-like immune cells and reveal an evolutionarily ancient link between mitochondrial dynamics and immune cell activation, with implications for understanding metabolic regulation of innate immunity in invertebrate models and beyond.

developmental biology↗

bioRxiv2020

Single-cell transcriptome maps of myeloid blood cell lineages in Drosophila

Drosophila lymph gland, the larval hematopoietic organ comprised of prohemocytes and hemocytes, has been a valuable model for understanding mechanisms underlying hematopoiesis and immunity. Three types of mature hemocytes have been characterized in the lymph gland: plasmatocytes, lamellocytes, and crystal cells, which are analogous to vertebrate myeloid cells. Here, we used single-cell RNA sequencing to comprehensively analyze heterogeneity of developing hemocytes in the lymph gland, and discovered novel hemocyte types, stem-like prohemocytes, and intermediate prohemocytes. Additionally, we identified the emergence of the lamellocyte lineage following active cellular immunity caused by wasp infestation. We unraveled similarities and differences between embryonically derived- and larval lymph gland hemocytes. Finally, the comparison of Drosophila lymph gland hemocytes and human immune cells highlights similarities between prohemocytes and hematopoietic stem cell, and between mature hemocytes and myeloid cells across species. Altogether, our study provides detailed insights on the development and evolution of hematopoiesis at single-cell resolution.

developmental biology↗