Sitravatinib potentiates immune checkpoint blockade in refractory cancer models
Wenting Du, Huocong Huang, Noah Sorrelle, Rolf A. Brekken
Wenting Du, Huocong Huang, Noah Sorrelle, Rolf A. Brekken
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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 5

Sitravatinib alters the immune landscape of KLN205 tumors to favor immune checkpoint blockade.

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Sitravatinib alters the immune landscape of KLN205 tumors to favor immun...
Flow cytometry of tumor-associated myeloid (A) and lymphoid cells (B) from mice bearing KLN205 tumors treated for 6 days with sitravatinib (sitra, n = 9–10/group). Monocytic myeloid-derived suppressor cells (M-MDSCs; CD11b+Ly6G–Ly6C+), PD-L1+ M-MDSCs, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs; CD11b+Ly6G+Ly6C+), PD-L1+ PMN-MDSC, neutrophils (CD11b+Ly6G+Ly6C–), macrophages (CD11b+Ly6G–Ly6C–F4/80+CD11c+MHCII+), Arg1+ macrophages (Macs), iNOS+ macrophages, CD3+ T cells, CD4+ T cells, CD8+ T cells, and PD-1+CTLA4+CD8+ T cells were analyzed. *P < 0.05, **P < 0.01 vs. control (Ctrl) by t test. (C) Flow cytometry of splenocytes from mice bearing KLN205 tumors treated with sitravatinib for 6 days (n = 9–10/group). CD3+ T cells, CD4+ T cells, CD8+ T cells, and Ki67+ CD8+ T cells were analyzed. *P < 0.05, **P < 0.01 vs. control by t test.