メモリーキラー細胞がメラノーマ患者の生存率を向上させることが判明(Memory killer cells can improve survival for melanoma patients)

2023-06-02 カロリンスカ研究所(KI)

<関連情報>

• https://news.ki.se/memory-killer-cells-can-improve-survival-for-melanoma-patients
• https://www.cell.com/immunity/fulltext/S1074-7613(23)00220-0

ヒト皮膚常在CD8+T細胞は、細胞毒性の誘導とインテグリンCD49aの発現にRUNX2およびRUNX3を必要とする Human skin-resident CD8+ T cells require RUNX2 and RUNX3 for induction of cytotoxicity and expression of the integrin CD49a

Beatrice Zitti,Elena Hoffer,Wenning Zheng,Ram Vinay Pandey,Heinrich Schlums,Giovanna Perinetti Casoni,Irene Fusi,Lien Nguyen,Jaanika Kärner,Efthymia Kokkinou,Anna Carrasco,Jessica Gahm,Marcus Ehrström,Staffan Happaniemi,Åsa V. Keita,Charlotte R.H. Hedin,Jenny Mjösberg,Liv Eidsmo,Yenan T. Bryceson
Immunity  Published:June 02, 2023
DOI:https://doi.org/10.1016/j.immuni.2023.05.003

Highlights

•Accessible chromatin in epidermal CD49a⁺ T_RM cells is enriched for RUNT and SMAD motifs
•Cytotoxic CD49a⁺ T_RM clones are represented in blood CD8⁺CD45RA^–CD62L⁺ T cells
•RUNX2 and RUNX3 activity promotes CD49a expression and cytotoxicity upon differentiation
•Epidermal CD49a⁺ T_RM gene signature correlates with better survival in melanoma

Summary

The integrin CD49a marks highly cytotoxic epidermal-tissue-resident memory (T_RM) cells, but their differentiation from circulating populations remains poorly defined. We demonstrate enrichment of RUNT family transcription-factor-binding motifs in human epidermal CD8⁺CD103⁺CD49a⁺ T_RM cells, paralleled by high RUNX2 and RUNX3 protein expression. Sequencing of paired skin and blood samples revealed clonal overlap between epidermal CD8⁺CD103⁺CD49a⁺ T_RM cells and circulating memory CD8⁺CD45RA^–CD62L⁺ T cells. In vitro stimulation of circulating CD8⁺CD45RA^–CD62L⁺ T cells with IL-15 and TGF-β induced CD49a expression and cytotoxic transcriptional profiles in a RUNX2- and RUNX3-dependent manner. We therefore identified a reservoir of circulating cells with cytotoxic T_RM potential. In melanoma patients, high RUNX2, but not RUNX3, transcription correlated with a cytotoxic CD8⁺CD103⁺CD49a⁺ T_RM cell signature and improved patient survival. Together, our results indicate that combined RUNX2 and RUNX3 activity promotes the differentiation of cytotoxic CD8⁺CD103⁺CD49a⁺ T_RM cells, providing immunosurveillance of infected and malignant cells.