Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases

Abstract

Assumptions that liver immune cells and immunosuppressive pathways are similar to their counterparts in other spaces have led to gaps in our understanding of intrahepatic neoplasm aggressiveness. Myeloid-derived suppressor cells (MDSCs) are potent inhibitors of antitumor immunity and pose a major obstacle to solid tumor treatment. Liver MDSCs (L-MDSCs) associated with liver metastases (LM) are particularly problematic by contributing to intrahepatic immunosuppression that promotes tumor progression. L-MDSCs have been reported to expand in response to granulocyte-macrophages colony-stimulating factor (GM-CSF) and suppress antitumor immunity in LM. To extend these findings, we examined mechanisms of intrahepatic immunosuppression exploited by L-MDSCs. We found that the majority of L-MDSCs co-expressed GM-CSF receptor (GM-CSF-R), indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PD-L1), while demonstrating high levels of signal transducer and activator of transcription factor 3 (STAT3) activation. GM-CSF-secreting tumor cells induced STAT3 phosphorylation in L-MDSCs in addition to expression of IDO and PD-L1. GM-CSF or GM-CSF-R blockade markedly reduced L-MDSC IDO and PD-L1 expression, implicating tumor-derived GM-CSF in supporting L-MDSC-immunoinhibitory molecule expression. Small-molecule inhibitors of Janus-activated kinase 2 (JAK2) and STAT3 also dramatically diminished IDO and PD-L1 expression in L-MDSCs. We determined that STAT3 exerts transcriptional control over L-MDSC IDO and PD-L1 expression by binding to the IDO1 and PD-L1 promoters. Our data suggest that the GM-CSF/JAK2/STAT3 axis in L-MDSCs drives immunosuppression in a model of LM and blockade of this pathway may enable rescue of intrahepatic antitumor immunity.

The STAT3 inhibitor galiellalactone inhibits the generation of MDSC‐like monocytes by prostate cancer cells and decreases immunosuppressive and tumorigenic factors

“…Galiellalactone inhibited IDO expression in monocytes, suggesting that galiellalactone may prevent immunosuppressive activities. It has previously been shown that IDO is upregulated by IL6 and GM‐CSF in MDSCs via activation of STAT3 and that STAT3 inhibition decreased this immunosuppressive activity of MDSCs . Arginase‐1 expression and activity in monocytes and MDSCs varies considerably between individuals, which may explain why we did not find a consistent effect on arginase‐1 expression in this study.…”

Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-α

“…Previous studies have described factors spontaneously secreted by tumor cells that led to TNF-α production by TAM [36, 37]. These factors were also reported to stimulate macrophages to produce TNF-α in a TLR2-dependent manner.…”

Chemotherapy induces tumor immune evasion by upregulation of programmed cell death ligand 1 expression in bone marrow stromal cells

“…It is possible that in GM-CSF might also come from tumor cells and other cell types in vivo. Interestingly, a recent study showed that GM-CSF secreted from tumor cells could promote PD-L1 expression in liver myeloidderived suppressor cells through Janus-activated kinase 2 (JAK2)-mediated activation of signal transducer and activator of transcription 3 (STAT3), which was able to bind to PD-L1 promoter and enhance its transcription (Thorn et al, 2016). Thus, endogenous GM-CSF from tumor cells could promote PD-L1 expression via the GM-CSF/JAK/STAT3 axis.…”