Disulfiram bolsters T‐cell anti‐tumor immunity through direct activation of LCK‐mediated TCR signaling

Abstract

Activation of the T-cell antigen receptor (TCR)-CD3 complex is critical to induce the anti-tumor response of CD8 + T cells. Here, we found that disulfiram (DSF), an FDA-approved drug previously used to treat alcohol dependency, directly activates TCR signaling. Mechanistically, DSF covalently binds to Cys20/Cys23 residues of lymphocyte-specific protein tyrosine kinase (LCK) and enhances its tyrosine 394 phosphorylation, thereby promoting LCK kinase activity and boosting effector T cell function, interleukin-2 production, metabolic reprogramming, and proliferation. Furthermore, our in vivo data revealed that DSF promotes anti-tumor immunity against both melanoma and colon cancer in mice by activating CD8 + T cells, and this effect was enhanced by anti-PD-1 co-treatment. We conclude that DSF directly activates LCK-mediated TCR signaling to induce strong anti-tumor immunity, providing novel molecular insights into the therapeutic effect of DSF on cancer.

Disulfiram's journey from rubber vulcanization to T‐cell activation

“…The new mechanistic knowledge reported by Wang et al (2022) suggests an additional use for disulfiram, a repurposed drug with an established safety profile, in cancer patients. Its direct activation of Lck is new, and if combined with the direct antitumor effect of its reactive metabolite complexed with copper (CuET), it could play a major role in treating cancer patients.…”

“…The data by Wang et al (2022) compellingly show that disulfiram and CuET both activate Lck and induce classical effector T (Teff) cells hallmarked by IL-2 production and proliferation (Fig 1A). However, whereas CuET was also cytotoxic, disulfiram did not negatively affect cell viability.…”

“…New evidence also shows that Lck can be bound or not bound (free) to the CD4 and CD8 coreceptors in thymocytes and T cells, with free Lck having higher mobility and activity compared with coreceptor‐bound Lck (Wei et al , 2020). In this issue, Wang et al (2022) provide evidence that T cells can also be activated via direct binding of the 60‐year‐old alcohol deterrent drug Antabuse (disulfiram) to Cys 20 /Cys 23 of Lck, enhancing Tyr 394 phosphorylation, boosting IL‐2 production, T‐cell proliferation, and effector function. These results are quite unexpected and formidably interesting.…”

“…Besides these considerations, an important point is whether disulfiram can be used in combination with immune checkpoint inhibitors to enhance the antitumor response and tumor protection. Wang et al (2022) show that disulfiram can synergize with anti‐PD‐1 antibodies in mice, but the beneficial effect on survival was not significant over disulfiram only. Perhaps, the results are not surprising as anti‐PD‐1 and disulfiram have an overlapping mechanism of action, that is, Lck‐mediated TCR activation (Arulraj & Barik, 2018).…”

“…The new mechanistic knowledge reported by Wang et al (2022) and if combined with the direct antitumor effect of its reactive metabolite complexed with copper (CuET), it could play a major role in treating cancer patients. Arguably, the newest aspect may lay in a potential synergy between disulfiram and secondgeneration immune checkpoint inhibitors.…”