Pan-TAM tyrosine kinase inhibitor BMS-777607 Enhances Anti-PD-1 mAb efficacy in a murine model of triple-negative breast cancer

Canan Kasikara, Viralkumar Davra, David Calianese, Ke Geng, Thomas E. Spires, Michael Quigley, Michael Wichroski, Ganapathy Sriram, Lucia Suarez-Lopez, Michael B. Yaffe, Sergei V. Kotenko, Mariana S. De Lorenzo, Raymond B. Birge

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Tyro3, Axl, and Mertk (TAM) represent a family of homologous tyrosine kinase receptors known for their functional role in phosphatidylserine (PS)-dependent clearance of apoptotic cells and also for their immune modulatory functions in the resolution of inflammation. Previous studies in our laboratory have shown that Gas6/PS-mediated activation of TAM receptors on tumor cells leads to subsequent upregulation of PD-L1, defining a putative PS!TAMreceptor!PD-L1 inhibitory signaling axis in the cancer microenvironment that may promote tolerance. In this study, we tested combinations of TAM inhibitors and PD-1 mAbs in a syngeneic orthotopic E0771 murine triple-negative breast cancer model, whereby tumor-bearing mice were treated with pan-TAM kinase inhibitor (BMS-777607) or anti-PD-1 alone or in combination. Tyro3, Axl, and Mertk were differentially expressed on multiple cell subtypes in the tumor microenvironment. Although monotherapeutic administration of either pan-TAM kinase inhibitor (BMS-777607) or anti- PD-1 mAb therapy showed partial antitumor activity, combined treatment of BMS-777607 with anti-PD-1 significantly decreased tumor growth and incidence of lung metastasis. Moreover, combined treatment with BMS-777607 and anti-PD-1 showed increased infiltration of immune stimulatory T cells versus either monotherapy treatment alone. RNA NanoString profiling showed enhanced infiltration of antitumor effector T cells and a skewed immunogenic immune profile. Proinflammatory cytokines increased with combinational treatment. Together, these studies indicate that pan-TAM inhibitor BMS-777607 cooperates with anti-PD-1 in a syngeneic mouse model for triple-negative breast cancer and highlights the clinical potential for this combined therapy. Significance: These findings show that pan-inhibition of TAM receptors in combination with anti-PD-1 may have clinical value as cancer therapeutics to promote an inflammatory tumor microenvironment and improve host antitumor immunity.

Original languageEnglish (US)
Pages (from-to)2669-2683
Number of pages15
JournalCancer Research
Volume79
Issue number10
DOIs
StatePublished - 2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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