Galunisertib Drives Treg Fragility and Promotes Dendritic Cell-Mediated Immunity against Experimental Lymphoma

• Main Authors: Sumit Kumar Hira, Abhinandan Rej, Ankush Paladhi, Ranjeet Singh, Jayasree Saha, Indrani Mondal, Sankar Bhattacharyya, Partha Pratim Manna
• Format: Article
• Language: English
• Published: Elsevier 2020-10-01
• Series: iScience
• Subjects: Immunology; Immunity; Cancer
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004220308154

Summary: Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-β receptor-I activation, currently under clinical trial in a variety of cancers. We have tested the combined effects of galunisertib- and interleukin-15-activated dendritic cells in an aggressive and highly metastatic murine lymphoma. Based on the tumor-draining lymph node architecture, and its histology, the combination therapy results in better prognosis, including disappearance of the disease-exacerbating regulatory T cells. Our data suggest that galunisertib significantly enhances the success of immunotherapy with IL-15-activated dendritic cells by limiting the regulatory T cells generation with consequent downregulation of regulatory T cells in the tumor-draining lymph nodes and vascularized organ like spleen. This is also associated with consistent loss p-SMAD2 and downregulation of Neuropilin-1, leading to better prognosis and positive outcome. These results connect the role of combined therapy with the consequent elimination of disease-exacerbating T regulatory cells in a metastatic murine lymphoma.