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Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients.

ABSTRACT: The immune modulatory effect of tivozanib, a tyrosine kinase inhibitor, and the underlying immune mechanisms impacting survival of HCC patients have not been investigated. Pre-clinical studies have shown that tivozanib reduces Tregs and MDSCs accumulation through inhibition of c-Kit/SCF axis. We rationalized that c-Kit/SCF axis antagonism by tivozanib may reverse tumor-induced immune suppression in HCC patients. The frequency of circulating Tregs, MDSCs, CTLA-4⁺Tregs, PD-1⁺T cells, c-Kit⁺pERK-2⁺Tregs, and c-Kit⁺pERK-2⁺MDSCs were quantified in HCC patients at baseline and two time points during tivozanib treatment. We report for the first time that reduction in Tregs after tivozanib treatment and increased levels of baseline CD4⁺PD-1⁺T cells correlated with significant improvement in overall survival (OS) of the patients and these signatures may be potential biomarkers of prognostic significance. This immune modulation resulted from tivozanib-mediated blockade of c-Kit/SCF signaling, impacting ERK2 phosphorylation on Tregs and MDSCs. Low pre-treatment CD4⁺T cells: Treg ratio and reduction in the frequencies of Foxp3⁺c-Kit⁺pERK⁺Tregs after tivozanib treatment correlated significantly with progression free survival. In a comparative analysis of tivozanib vs sorafenib treatment in HCC patients, we demonstrate that decrease in the baseline numbers or frequencies of Foxp3⁺Tregs, MDSCs and exhausted T cells was significantly greater following tivozanib treatment. Additionally, greater increase in CD4⁺T cell: Treg ratio after tivozanib treatment was associated with significant improvement in OS compared to sorafenib treatment, highlighting the greater efficacy of tivozanib. These insights may help identify patients who likely would benefit from c-Kit/SCF antagonism and inform efforts to improve the efficacy of tivozanib in combination with immunotherapy.

SUBMITTER: Kalathil SG

PROVIDER: S-EPMC7553535 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUNDSorafenib has been shown to reduce the extent of immunosuppression in patients with hepatocellular carcinoma (HCC). The rationale of this investigation was to identify biomarkers that can predict treatment efficacy of sorafenib in HCC patients and to unravel the mechanism by which sorafenib impedes immune suppression mediated by distinct immunosuppressive cell subsets.METHODSWith informed consent, blood samples were collected from 30 patients with advanced HCC, at baseline and 2 time points after initiation of sorafenib treatment. The frequency of PD-1+ T cells, ERK2 phosphorylation on flt-3+ Tregs and MDSCs, and T effector cell function were quantified by using flow cytometry.RESULTSElevated levels of CD8+Ki67+ T cells producing IFN-γ were associated with improved progression-free survival and overall survival (OS). High frequencies of these T cells were correlated with significantly reduced risk of death over time. Patients with an increased pretreatment T effector/Treg ratio showed significant improvement in OS. ERK+flt-3+ Tregs and MDSCs were significantly decreased after sorafenib therapy. Increased numbers of baseline flt-3+p-ERK+ MDSCs were associated with survival benefit of patients.CONCLUSIONA high baseline CD4+ T effector/Treg ratio is a potential biomarker of prognostic significance in HCC. CD8+Ki67+ T cells producing IFN-γ are a key biomarker of response to sorafenib therapy resulting in survival benefit. The immune modulation resulted from sorafenib-mediated blockade of signaling through the VEGF/VEGFR/flt-3 pathway, affecting ERK phosphorylation. These insights may help identify patients who likely would benefit from VEGFR antagonism and inform efforts to improve the efficacy of sorafenib in combination with immunotherapy.TRIAL REGISTRATIONNCT02072486.FUNDINGNational Comprehensive Cancer Network Oncology Research Program from general research support provided by Bayer US LLC (NCCNSORA0002), National Cancer Institute grant P30CA016056, and pilot funds from Roswell Park Alliance Foundation.

Project description:Stem cell factor (SCF), the ligand of c-kit, is a key cytokine for hematopoiesis. Hematopoietic precursors express c-kit, whereas differentiated cells of hematopoietic lineage are negative for this receptor, with the exception of NK cells, mast cells, and a few others. While it has long been recognized that dendritic cells (DCs) can express c-kit, several questions remain concerning the SCF/c-kit axis in DCs. This is particularly relevant for DCs found in those organs wherein SCF is highly expressed, including the bone marrow (BM). We characterized c-kit expression by conventional DCs (cDCs) from BM and demonstrated a higher proportion of c-kit+ cells among type 1 cDC subsets (cDC1s) than type 2 cDC subsets (cDC2s) in both humans and mice, whereas similar levels of c-kit expression were observed in cDC1s and cDC2s from mouse spleen. To further study c-kit regulation, DCs were generated with granulocyte-macrophage colony-stimulating factor (GM-CSF) from mouse BM, a widely used protocol. CD11c+ cells were purified from pooled non-adherent and slightly adherent cells collected after 7?days of culture, thus obtaining highly purified BM-derived DCs (BMdDCs). BMdDCs contained a small fraction of c-kit+ cells, and by replating them for 2?days with GM-CSF, we obtained a homogeneous population of c-kit+ CD40hi MHCIIhi cells. Not only did BMdDCs express c-kit but they also produced SCF, and both were striking upregulated if GM-CSF was omitted after replating. Furthermore, a small but significant reduction in BMdDC survival was observed upon SCF silencing. Incubation of BMdDCs with SCF did not modulate antigen presentation ability of these cells, nor it did regulate their membrane expression of the chemokine receptor CXCR4. We conclude that the SCF/c-kit-mediated prosurvival circuit may have been overlooked because of the prominent use of GM-CSF in DC cultures in vitro, including those human DC cultures destined for the clinics. We speculate that DCs more prominently rely on SCF in vivo in some microenvironments, with potential implications for graft-versus-host disease and antitumor immunity.

Project description:INTRODUCTION: Breast cancer remains the second leading cause of cancer-related deaths for women in the United States. Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the microenvironment, especially those associated with chronic inflammation. We recently reported that mice with autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer. In this study, we evaluated the mechanism underlying the increased metastasis. METHODS: We used two mouse models; one that develops spontaneous autoimmune arthritis (SKG mice) injected with metastatic breast cancer cells (4T1), and another that develops spontaneous breast cancer (MMTV-PyV MT mice) injected with type II collagen to induce autoimmune arthritis. Mast cell levels and metastasis were monitored. RESULTS: First, we confirmed that breast tumor-bearing arthritic mice have a significantly higher incidence of bone and lung metastasis than do their nonarthritic counterparts. Next, we showed increased recruitment of mast cells within the primary tumor of arthritic mice, which facilitates metastasis. Next, we report that arthritic mice without any tumors have higher numbers of mast cells in the bones and lungs, which may be the underlying cause for the enhanced lung and bone metastases observed in the arthritic mice. Next, we showed that once the tumor cells populate the metastatic niches (bones and lungs), they further increase the mast cell population within the niche and assist in enhancing metastasis. This may primarily be due to the interaction of c-Kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells. Finally, we showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis. CONCLUSION: This is the first report to show that mast cells may play a critical role in remodeling not only the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis through SCF/cKit interaction in breast cancer with arthritis.

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Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients.

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