Aspirin and immunotherapy: a Faustian bargain?
Eric A. Goethe, … , Amy B. Heimberger, Ganesh Rao
Eric A. Goethe, … , Amy B. Heimberger, Ganesh Rao
Published May 1, 2023
Citation Information: J Clin Invest. 2023;133(9):e169598. https://doi.org/10.1172/JCI169598.
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Commentary

Aspirin and immunotherapy: a Faustian bargain?

Abstract

Fibrinogen-like protein 1 (FGL1) has been associated with improved survival in hepatocellular carcinoma (HCC). However, recent evidence suggests that FGL1 may bind to surface receptors on lymphocytes and induce immune senescence. In this issue of the JCI, Lin and co-authors show that FGL1 may be acetylated by aspirin and targeted for degradation, which is associated with increased antitumor immunity and improved survival. Similar findings were obtained with inhibitors of sirtuin 2 (SIRT2), a histone deacetylase. These findings expand our current understanding of the role of FGL1 in cancer and provide an impetus for the evaluation of alternative immunotherapy combinations in HCC.

Authors

Eric A. Goethe, Amy B. Heimberger, Ganesh Rao

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Figure 1

Acetylation of FGL1 has a regulatory role in HCC antitumor immunity.

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Acetylation of FGL1 has a regulatory role in HCC antitumor immunity. Ace...
Acetylation of FGL1 at Lys-98 reduces the levels of FGL1 in HCC cells due to increased proteasomal degradation. The NAD+-dependent deacetylase SIRT2 decreases FGL1 acetylation, which facilitates interaction between LAG-3 to promote evasion from immune surveillance. In contrast, compounds that increase acetylated FGL1, including the SIRT2 inhibitor AGK2, NAM, and aspirin, increase FGL1 degradation and antitumor immunity via T cell–mediated killing.