Sitravatinib potentiates immune checkpoint blockade in refractory cancer models
Wenting Du, … , Noah Sorrelle, Rolf A. Brekken
Wenting Du, … , Noah Sorrelle, Rolf A. Brekken
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e124184. https://doi.org/10.1172/jci.insight.124184.
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Categories: Research Article Oncology Therapeutics

Sitravatinib potentiates immune checkpoint blockade in refractory cancer models

Abstract

Immune checkpoint blockade has achieved significant therapeutic success for a subset of cancer patients; however, a large portion of cancer patients do not respond. Unresponsive tumors are characterized as being immunologically “cold,” indicating that these tumors lack tumor antigen-specific primed cytotoxic T cells. Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MerTK) and split tyrosine-kinase domain–containing receptors (VEGFR and PDGFR families and KIT) plus RET and MET, targets that contribute to the immunosuppressive tumor microenvironment. We report that sitravatinib has potent antitumor activity by targeting the tumor microenvironment, resulting in innate and adaptive immune cell changes that augment immune checkpoint blockade. These results suggest that sitravatinib has the potential to combat resistance to immune checkpoint blockade and expand the number of cancer patients that are responsive to immune therapy.

Authors

Wenting Du, Huocong Huang, Noah Sorrelle, Rolf A. Brekken

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Figure 1

MerTK inhibition with sitravatinib directly affects macrophage phenotype.

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MerTK inhibition with sitravatinib directly affects macrophage phenotype...
The expression of M1-type macrophage markers Tnfα, Il-6, and Il-12 (A) and M2-type macrophage markers Arg1, Ym-1, and Fizz-1 (B) in bone marrow–derived macrophages (BMDMs). BMDMs were harvested from WT C57BL/6 or MerTK–/– (green) mice, stimulated with 20 ng/ml LPS for 2 hours (A) or 40 ng/ml IL-4 for 18 hours (B). Each stimulation was performed with or without sitravatinib (12.5, 50, 200, and 800 nM) in the presence (red and green) or absence (blue) of KLN205 conditioned media (CM). The expression level of TNF-α, IL-6, IL-12, arginase 1, YM-1, and Fizz-1 was determined by q-PCR. Three independent experiments using duplicate samples were performed. Data are displayed as fold change normalized to control in each condition (mean ± SD). For each marker, the top graph is the basal expression change in each stimulation condition, and the bottom graph is expression change caused by different concentrations of sitravatinib in each condition. *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001 vs. the control (WT macrophages without stimulation) or DMSO (0 nM) in each condition by ANOVA.