2024-01-08 カリフォルニア大学サンタバーバラ校(UCSB)
hoto Credit ChatGPT4, prompt by Denise Montell
A blue macrophage engulfs a magenta lymphocyte, as rendered by ChatGPT4.
◆異なる生物の視点からの細胞生物学の基本的な理解から出発し、ヒトの免疫不全を解明し、最終的にはがん治療に結びつくという重要な研究結果が得られました。
<関連情報>
- https://news.ucsb.edu/2024/021313/when-bad-cells-go-good-harnessing-cellular-cannibalism-cancer-treatment
- https://www.pnas.org/doi/abs/10.1073/pnas.2310221120
高活性Racは生きた標的細胞の共食いを刺激し、CAR-Mを介したがん細胞の殺傷を促進する Hyperactive Rac stimulates cannibalism of living target cells and enhances CAR-M-mediated cancer cell killing
Abhinava K. Mishra, Melanie Rodriguez, Alba Yurani Torres, Morgan Smith, Anthony Rodriguez, Annalise Bond, Meghan A. Morrissey, and Denise J. Montell
Proceedings of the National Academy of Sciences Published:December 18, 2023
DOI:https://doi.org/10.1073/pnas.2310221120
Significance
The small GTPase Rac2 is a key regulator of immune cell shape and function. Hyperactivating Rac2 mutations cause rare human immunodeficiencies though the underlying mechanisms are unclear. Based on fundamental cell biology in the fruit fly, we found that hyperactive Rac causes cells to eat other cells alive. We show that activated Rac2 also drives mouse and human macrophages to cannibalize activated T cells and that active Rac enhances engulfment of cancer cell targets by chimeric antigen receptor macrophages (CAR-M). These results suggest that Rac2E62K-stimulated cannibalism may contribute to Rac2+/E62K human immunodeficiency and enhance CAR-M cancer immunotherapy.
Abstract
The 21kD GTPase Rac is an evolutionarily ancient regulator of cell shape and behavior. Rac2 is predominantly expressed in hematopoietic cells where it is essential for survival and motility. The hyperactivating mutation Rac2E62K also causes human immunodeficiency, although the mechanism remains unexplained. Here, we report that in Drosophila, hyperactivating Rac stimulates ovarian cells to cannibalize neighboring cells, destroying the tissue. We then show that hyperactive Rac2E62K stimulates human HL60-derived macrophage-like cells to engulf and kill living T cell leukemia cells. Primary mouse Rac2+/E62K bone-marrow-derived macrophages also cannibalize primary Rac2+/E62K T cells due to a combination of macrophage hyperactivity and T cell hypersensitivity to engulfment. Additionally, Rac2+/E62K macrophages non-autonomously stimulate wild-type macrophages to engulf T cells. Rac2E62K also enhances engulfment of target cancer cells by chimeric antigen receptor-expressing macrophages (CAR-M) in a CAR-dependent manner. We propose that Rac-mediated cell cannibalism may contribute to Rac2+/E62K human immunodeficiency and enhance CAR-M cancer immunotherapy.
