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- W4313373657 abstract "Abstract Although immune checkpoint blockade (ICB) has emerged as a promising cancer therapy, a majority of cancers, such as pancreatic cancer and triple negative breast cancer, fail to respond to ICB. A potential mechanism is the accumulation of transforming growth factor-β1 (TGFβ1) in tumor microenvironment (TME) which drives immune dysfunction by inducing regulatory T cells (Treg), excluding and inhibiting the function of effector CD8+ T cells. Glycoprotein-A repetitions predominant protein (GARP) is a cell surface docking and activating receptor for latent TGFβ1 and highly expressed in breast cancer cells, Tregs and platelets. Previous work from our lab has demonstrated a critical role for GARP in dampening anti-tumor immunity via TGFβ1 pathway. To validate if GARP is a therapeutic target, we generated an anti-human GARP antibody (4D3). We found that 4D3 blocked GARP-latent TGFβ1 interaction and limited active TGFβ1 release. We expressed human GARP in murine 4T1 breast cancer cells. In this orthotopic syngeneic mouse tumor model, combination therapy with 4D3 and anti-PD1 antibody suppressed tumor growth and metastasis more effectively than treatment with either agent alone, resulting in significantly enhanced survival. Mechanistically, the combination therapy reduced p-SMAD3 expression as well as collagen deposition in the TME. In addition, 4D3 treatment reduced tumor-associated macrophages and their PD-L1 expression. Collectively, our preclinical data demonstrated that simultaneous blockade of the PD1 and GARP-TGFβ1 axis elicits potent and superior anti-tumor efficacy relative to monotherapies, suggesting a potentially more effective strategy against cancers that are resistant to current immune checkpoint blockade." @default.
- W4313373657 created "2023-01-06" @default.
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- W4313373657 date "2020-05-01" @default.
- W4313373657 modified "2023-09-27" @default.
- W4313373657 title "Targeting GARP-TGFβ axis enhances anti-tumor efficacy of immune checkpoint blockade therapy" @default.
- W4313373657 doi "https://doi.org/10.4049/jimmunol.204.supp.241.35" @default.
- W4313373657 hasPublicationYear "2020" @default.
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