SLAMF7 promotes TCRαβ⁺ double negative T cell antitumor activity through enhancing glutamine metabolism

TCRαβ⁺ double negative T cells (DNT) have recently gained attention for their antitumor activity. Adoptive DNT therapy has emerged as a promising cancer immunotherapy due to its potent cytotoxic function and lack of graft-versus-host-disease. However, the intrinsic mechanisms regulating DNT antitumor functions remain unclear.

Signaling lymphocytic activation molecule factor 7 (SLAMF7) expression in murine and human DNT were evaluated. The antitumor activities were compared between SLAMF7⁺ and SLAMF7^- DNT both in vivo and in vitro. Further, metabolomics analysis was performed to reveal the underlying mechanism by which SLAMF7 promotes DNT antitumor cytotoxicity.

The expression of SLAMF7 was markedly increased on DNT upon activation. SLAMF7⁺ DNT exhibited superior antitumor capacity both in vitro and in vivo compared with SLAMF7^- DNT. Mechanistically, SLAMF7 enhanced antitumor activity through ligand-independent and ligand-dependent dual manners. Firstly, SLAMF7 could upregulate GPT2/SLC1A5-mediated glutamine metabolism by activating ERK signaling pathway in DNT, thereby supporting mitochondrial fitness, increasing ATP production, enhancing the expression of effector molecules such as granzyme B and perforin, and promoting antitumor activity of DNT against tumor cells independent of homotypic ligand-receptor interactions. Secondly, DNT showed superior antitumor cytotoxicity against SLAMF7-expressing tumor cells because SLAMF7-SLAMF7 interaction between DNT and SLAMF7-expressing tumor cells promoted DNT cell degranulation. Furthermore, SLAMF7 was also highly expressed in human DNT, and its dual antitumor roles in human DNT were also validated.

SLAMF7 is a key regulator of DNT-mediated cytotoxicity and a promising target for improving DNT cell function in cancer therapy.