The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib

Abstract

Increased numbers of immunosuppressive myeloid derived suppressor cells (MDSCs) correlate with a poor prognosis in cancer patients. Tyrosine kinase inhibitors (TKIs) are used as standard therapy for the treatment of several neoplastic diseases. However, TKIs not only exert effects on the malignant cell clone itself but also affect immune cells. Here, we investigate the effect of TKIs on the induction of MDSCs that differentiate from mature human monocytes using a new in vitro model of MDSC induction through activated hepatic stellate cells (HSCs). We show that frequencies of monocytic CD14(+)HLA-DR(-/low) MDSCs derived from mature monocytes were significantly and dose-dependently reduced in the presence of dasatinib, nilotinib and sorafenib, whereas sunitinib had no effect. These regulatory effects were only observed when TKIs were present during the early induction phase of MDSCs through activated HSCs, whereas already differentiated MDSCs were not further influenced by TKIs. Neither the MAPK nor the NFκB pathway was modulated in MDSCs when any of the TKIs was applied. When functional analyses were performed, we found that myeloid cells treated with sorafenib, nilotinib or dasatinib, but not sunitinib, displayed decreased suppressive capacity with regard to CD8+ T cell proliferation. Our results indicate that sorafenib, nilotinib and dasatinib, but not sunitinib, decrease the HSC-mediated differentiation of monocytes into functional MDSCs. Therefore, treatment of cancer patients with these TKIs may in addition to having a direct effect on cancer cells also prevent the differentiation of monocytes into MDSCs and thereby differentially modulate the success of immunotherapeutic or other anti-cancer approaches.

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

“…11 MDSCs could be induced from mature human monocytes through HSCs dose-dependently. 35 Furthermore, activated human hepatic stellate cells induce myeloid-derived suppressor cells from peripheral blood monocytes in a CD44dependent fashion. 36 Bone marrow cells cultured with HSC-CM express lower levels of CD11c, CD80, CD86, and MHCII ( Figure 2B), suggesting that HSCs inhibit the differentiation of IMCs into mature myeloid cells and increase the expansion of MDSCs.…”

Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages

“…Our data suggest that imatinib and nilotinib could decrease in vivo the half-life of circulating monocytes, as well as their recruitment and macrophage differentiation in tissues, possibly reducing the generation of macrophages that in the tumor microenvironment might acquire M2 tumor-promoting function. Interestingly, it has been shown that imatinib inhibited the early phase of the differentiation of myeloid-derived suppressor cells and reduced their number in CML patients (48), whereas it did not affect differentiation toward dendritic cells (49).…”

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma

“…88,95,96 Other MKIs (lenvatinib, regorafenib, and cabozantinib) have also demonstrated antitumor immune activity in various pre-clinical models. 78,79,81,97 While many of the immunomodulatory effects may be linked to the VEGFR-inhibitory property of these MKIs, multiple cellular and soluble factors in the tumour microenvironment may mediate their immunomodulatory effects (Fig. 1).…”