Pan-TAM Tyrosine Kinase Inhibitor BMS-777607 Enhances Anti–PD-1 mAb Efficacy in a Murine Model of Triple-Negative Breast Cancer
| العنوان: | Pan-TAM Tyrosine Kinase Inhibitor BMS-777607 Enhances Anti–PD-1 mAb Efficacy in a Murine Model of Triple-Negative Breast Cancer |
|---|---|
| المؤلفون: | Michael Wichroski, Lucia Suarez-Lopez, Raymond B. Birge, Canan Kasikara, Mariana S. De Lorenzo, Thomas E. Spires, Michael B. Yaffe, Viralkumar Davra, Ganapathy Sriram, Sergei V. Kotenko, Ke Geng, Michael Quigley, David Calianese |
| المصدر: | Cancer Research. 79:2669-2683 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Pyridones, medicine.drug_class, Programmed Cell Death 1 Receptor, Aminopyridines, Triple Negative Breast Neoplasms, Receptor tyrosine kinase, Tyrosine-kinase inhibitor, Proinflammatory cytokine, Mice, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Immune system, Cell Line, Tumor, Tumor Microenvironment, medicine, Animals, Triple-negative breast cancer, Tumor microenvironment, biology, Chemistry, GAS6, Antibodies, Monoclonal, Protein-Tyrosine Kinases, MERTK, Xenograft Model Antitumor Assays, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Female |
| الوصف: | 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→TAM receptor→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. |
| تدمد: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-18-2614 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::698ce405abe2e33b3b44bd20fbfe1bbd https://doi.org/10.1158/0008-5472.can-18-2614 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....698ce405abe2e33b3b44bd20fbfe1bbd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
|---|---|
| DOI: | 10.1158/0008-5472.can-18-2614 |