Skin-resident γδ T cells mediate potent and selective antitumor cytotoxicity through directed chemotactic migration and mobilization of cytotoxic granules.

in The Journal of investigative dermatology by Jiacai Yang, Zhihui Liu, Xiaohong Hu, Xiaorong Zhang, Yong Huang, Yunxia Chen, Cheng Chen, Ruoyu Shang, Yuanyang Tang, Wengang Hu, Jue Wang, Han-Ming Shen, Jun Hu, Weifeng He

TLDR

  • DETCs are a type of γδ T cell that can mediate potent and selective cytotoxicity against tumors, making them a promising target for cancer immunotherapy.

Abstract

Dendritic epidermal T cells (DETCs) are a unique subset of γδ T cells that reside predominantly in mouse epidermis, yet their antitumor functions remain enigmatic. Here we report that DETCs mediate potent and exquisitely selective cytotoxicity against diverse tumor types while sparing healthy cells. In vitro, DETCs induced apoptosis in melanoma, hepatoma, colon carcinoma and lymphoma lines in a dose- and time-dependent manner that required direct cell-cell contact. In vivo, adoptive DETC transfer significantly suppressed melanoma growth and metastasis while prolonging survival. Mechanistically, DETCs upregulated perforin/granzyme B expression upon tumor recognition, and inhibition of this pathway ablated cytotoxicity. DETCs selectively homed to and formed intimate contacts with tumor cells in vivo through directed chemotaxis and aggregation. Tumor engagement triggered pro-inflammatory DETC activation while dampening immunosuppressive factors in the microenvironment. Notably, mTOR signaling coupled tumor recognition to DETC trafficking, cytotoxicity and inflammatory programs, as rapamycin treatment impaired effector functions and therapeutic efficacy. Collectively, these findings establish DETCs as multidimensional antitumor effectors and provide insights for harnessing their unique biology for cancer immunotherapy.

Overview

  • The study investigates the antitumor functions of dendritic epidermal T cells (DETCs), a unique subset of γδ T cells that reside predominantly in mouse epidermis.
  • DETCs were found to mediate potent and selective cytotoxicity against diverse tumor types while sparing healthy cells.
  • The study aims to understand the mechanism of DETC-mediated antitumor activity and its potential for cancer immunotherapy.

Comparative Analysis & Findings

  • DETCs induced apoptosis in melanoma, hepatoma, colon carcinoma, and lymphoma lines in a dose- and time-dependent manner, requiring direct cell-cell contact.
  • In vivo adoptive DETC transfer significantly suppressed melanoma growth and metastasis while prolonging survival.
  • DETCs upregulated perforin/granzyme B expression upon tumor recognition, and inhibition of this pathway ablated cytotoxicity, suggesting a critical role for this pathway in mediating antitumor activity.

Implications and Future Directions

  • The study highlights the potential of DETCs as multidimensional antitumor effectors and provides insights for harnessing their unique biology for cancer immunotherapy.
  • Future studies should investigate the mechanisms by which DETCs selectively home to and interact with tumor cells, as well as the role of mTOR signaling in DETC trafficking and antitumor activity.
  • The findings suggest that targeted therapies aimed at enhancing DETC trafficking, cytotoxicity, and inflammatory programs may be effective in treating various cancers.
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