Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1

Abstract

T cells play a critical role in tumor immunosurveillance by eliminating newly transformed somatic cells. However, tumor cell variants can escape from immunological control after immunoediting, leading to tumor progression. Whether and how T cells respond to tumor growth remain unclear. Here, we found that tumor-infiltrating T cells exhibited persistently up-regulated expression of the activator protein 1 (AP-1) subunit c-Fos during tumor progression. The ectopic expression of c-Fos in T cells exacerbated tumor growth, whereas the T-cell-specific deletion of c-Fos reduced tumor malignancy. This unexpected immunosuppressive effect of c-Fos was mediated through the induced expression of immune inhibitory receptor programmed death 1 (PD-1) via the direct binding of c-Fos to the AP-1-binding site in the Pdcd1 (gene encoding PD-1) promoter. A knock-in mutation of this binding site abrogated PD-1 induction, augmented antitumor Tcell function and repressed tumor growth. Taken together, these findings indicate that T-cell c-Fos subsequently induces PD-1 expression in response to tumor progression and that disrupting such induction is essential for repression of tumor growth.antitumor immunity | T cell response | transactivation

CD4+ follicular helper T cell infiltration predicts breast cancer survival

“…Some earlier studies described lymphoid aggregates or organized lymphoid structures in tumors, including BC (81); however, their prognostic value has only recently been investigated in a study of non-small cell lung cancer, in which the number of mature DCs was used as an indicator for TLS (26), and in colorectal cancer, in which both lymphocyte aggregates (57) and active TLS, the latter identified and SN+S-treated donor cells in parallel with a decrease in JUN, FOSB, and ATF3 in the rested TIL, suggesting that their expression is induced when activated cells enter the tumor microenvironment. A recent study has shown that AP-1 (FOS) is persistently upregulated in infiltrating T cells during tumor progression in mice (51). FOS upregulation specifically induces PD-1 expression on CD4 and CD8 TIL, which mediates their suppression upon contact with PD-L1-expressing tumor cells.…”

STAT3, STAT4, NFATc1, and CTCF Regulate PD-1 through Multiple Novel Regulatory Regions in Murine T Cells

“…cFos was identified as a factor that binds to CR-B, a promoter proximal element that was necessary for maximal induction by NFATc1 (14). Additionally, an interferon-stimulated regulatory element (ISRE), located in CR-C, was reported to enhance and prolong PD-1 transcription upon T cell and macrophage activation (15, 16).…”

Small-Molecule Inhibition of PD-1 Transcription Is an Effective Alternative to Antibody Blockade in Cancer Therapy

“…Pdcd1 expression can be positively and negatively regulated by different transcription factors such as nuclear factor of activated T cells (NFAT), Forkhead box protein O1 (FoxO1), Notch, activator protein 1 (AP1), and B-lymphocyte maturation protein 1 (Blimp1; refs. [16][17][18][19]. Despite this, the identity of the upstream signaling event(s) that control PD-1 expression has been unclear.…”