Platelet-expressed immune checkpoint regulator GITRL in breast cancer

Abstract

Breast cancer is the leading cause of cancer-related death in women. Most subtypes of breast cancer are immunologically silent, which makes the immunotherapy of patients with advanced breast cancer particularly challenging and new targets are urgently needed. Platelets play an important role in tumor progression as they promote proliferation, chemotherapy resistance, stemness, invasion, and immune evasion of malignant cells. As a new target of immune checkpoint therapy, GITRL has attracted more and more attention. Little is known about the role of pGITRL in breast cancer. We assumed that pGITRL may serve as a biomarker and a potential immunotherapeutic target in breast cancer. Here, we conducted a comparative analysis of pGITRL in breast cancer patients. pGITRL expression was upregulated in breast cancer patients as compared to healthy donors and especially increased in cases of intermediate tumor stages, low proliferation index, and absence of metastasis. GITR expression on NK cells increased in breast cancer patients as compared to healthy donors. Moreover, GITRL expression was enhanced during platelet activation in breast cancer patients. The capacity of GITRL upregulation upon platelet activation associated with the basal GITRL expression on resting platelets in both breast cancer and healthy donor cohorts. GITRL expression was enhanced during megakaryopoiesis and particularly upregulated in the presence of soluble factors derived from breast cancer cells. All the findings may suggest enhanced pGITRL levels and increased capacity of pGITRL regulation upon platelet activation in breast cancer as part of a tumor-educated platelet phenotype. Based on our data, pGITRL may serve as a readily available biomarker and a potential immunotherapeutic target in breast cancer.