Journal
JCI INSIGHT
Volume 3, Issue 20, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.122591
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Funding
- NIH [U54HL119893, R01HL113032, R01HL134183, S10OD020054, P41CA196276, 1K01DK099405, T32 AI 007334-27, F31 DK112607]
- UC-CAI UCSF Catlyst2 [AB2664]
- University of California Office of the President Tobacco-Related Disease Research Program
- UCSF Liver Center [P30DK026743]
- Ibrahim El-Hefni Technical Training Foundation
- [R01DK093646]
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TGF-beta is a promising immunotherapeutic target. It is expressed ubiquitously in a latent form that must be activated to function. Determination of where and how latent TGF-beta (L-TGF-beta) is activated in the tumor microenvironment could facilitate cell- and mechanism-specific approaches to immunotherapeutically target TGF-beta. Binding of L-TGF-beta to integrin alpha v beta 8 results in activation of TGF-beta. We engineered and used alpha v beta 8 antibodies optimized for blocking or detection, which - respectively inhibit tumor growth in syngeneic tumor models or sensitively and specifically detect beta 8 in human tumors. Inhibition of alpha v beta 8 potentiates cytotoxic T cell responses and recruitment of immune cells to tumor centers - effects that are independent of PD-1/PD-L1. beta 8 is expressed on the cell surface at high levels by tumor cells, not immune cells, while the reverse is true of L-TGF-beta, suggesting that tumor cell alpha v beta 8 serves as a platform for activating cell-surface L-TGF-beta presented by immune cells. Transcriptome analysis of tumor-associated lymphoid cells reveals macrophages as a key cell type responsive to beta 8 inhibition with major increases in chemokine and tumor-eliminating genes. High beta 8 expression in tumor cells is seen in 20%-80% of various cancers, which rarely coincides with high PD-L1 expression. These data suggest tumor cell alpha v beta 8 is a PD-1/PD-L1-independent immunotherapeutic target.
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