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

Abstract

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.

Targeted delivery of galunisertib attenuates fibrogenesis in an integratedex vivorenal transplant and fibrosis model

“…We therefore tried eliminating these effect by performing ex vivo perfusion. As also observed in a previous study, we detected higher expression of TNF-α gene expression after treatment with galunisertib (19). However, galunisertib combined with TGFβ treatment reduced TNF-α expression.…”

Nanoscale Diamond-Based Formulation as an Immunomodulator and Potential Therapeutic for Lymphoma

“…Mouse splenic myeloid DCs (CD11c, MHC Class II, CD11b and CD8α) and T cells from normal, tumor-bearing or disease-free treated mice were isolated as described previously ( Hira et al, 2014 ). Purified CD4 + or CD8 + T cells were isolated as described previously ( Srivastava et al, 2017 ; Hira et al, 2020 ). Isolated DCs were further incubated with Ayu_ND (1 mg/ml) or LPS (5 mg/ml) for in vitro stimulation.…”

“…The MTT assay was used to determine cell proliferation as described previously ( Hira et al, 2014 ). CTL assays were performed as reported previously ( Hira et al, 2020 ). The details are in the methodology section of the supporting information.…”

“…DCs or T cells derived from normal, tumor-bearing (32 days post-tumor transplant) or vaccinated mice were stained for phenotypic analysis (i.e., surface expression of DC-specific markers, Treg status, CD8 + memory cell status, etc.) by flow cytometry as describe earlier ( Hira et al, 2020 ). The details are in the methodology section of the supporting information.…”

Advances of Tumorigenesis, Diagnosis at Early Stage, and Cellular Immunotherapy in Gastrointestinal Malignancies

“…Expression of Treg cells in biopsy represents a negative prognosis (43). Interestingly, in Hodgkin's lymphoma, Treg cells inhibit malignant cell growing, which show a good prognosis (44)(45)(46). More interestingly, gdT cells stained in the TME directly destroy transformed cells and upregulate activity of DCs, cytotoxic T cells, and NK cells in most malignant tumors (47)(48)(49)(50).…”