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Abstract
Background TGF-ß plays a key role in immune evasion as a critical regulator of both innate and adaptive tumor immunity and promotes broad immunosuppressive effects on numerous inflammatory cell subpopulations ultimately resulting in tumor immune tolerance and evasion.1 It has also been implicated in resistance to immune checkpoint therapies, and additive or synergistic effects of dual TGF-ß and PD-1 inhibition has been reported.2 3 A number of TGF-ß inhibitors are in clinical development with different modes of action. Most protein-based inhibitors are designed to block diffusible TGF-ß from interacting with its proximal signaling receptor TGF-ßR2 and includes monoclonal antibodies (Mabs) and receptor traps. This investigation compares inhibition of TGF-ß by a number of inhibitors and the integrin avß8 (C6D4) to assess their relative potential as cancer therapeutics.
Methods No reporter system currently exists to investigate the mechanistic basis of cell-intrinsic TGF-ß activation, whereby the L-TGF-ß presenting cell is also the cell that responds toTGF-ß signaling (figure 1). To build a cell-intrinsic TGF-ß activation system, TMLC cells were stably transfected with wild-type (WT) TGF-ß. Without co-transfecting GARP, TMLC do not present L-TGF-ß on their cell surface. When co-transfected with TGF-ß and GARP, high levels of cell surface expression of L-TGF-ß are detected. Additionally, to build a cell-intrinsic TGF-ß activation system which express a non-releasable form of TGF-ß, we mutated the L-TGF-ß furin cleavage site (R249A) and similarly expressed the L-TGF-ß(R249A)/GARP complex on the surface of TGF-ß reporter cells (TMLC). These cell-intrinsic TGF-ß activation systems were used to assess the relative abilities of Mabs avß8, TGF-ß, TGF-ßR2, GARP or TGF-ßR2 receptor trap to inhibit avß8-mediated TGF-ß activation.
Results avß8 exhibited superior inhibitory activity compared with other TGF-ß inhibitors, which was similar in both diffusible and non-diffusible models (figure 2). The biologic relevance of these finding was confirmed using CD4+ T-cells in place of the reporter cells where TGF-ß-dependent Treg generation was almost completely blocked by avß8 but was poorly inhibited by the other TGF-ß inhibitors.
Novel cell-intrinsic TGF-β reporter system
Inhibition curves showing inhibition of αvβ8-mediated TGF-β activation by various inhibitors including anti-β8 (C6D4) in a model of diffusible (A) or non-diffusible ((R249A mutant) L-TGF-β (B)
Conclusions In this study avß8 exhibited dramatic TGF-ß inhibitory activity compared with a wide range of inhibitors in development. Because integrin avß8 may direct TGF-ß signaling from within its latent complex, this may offer an advantage for target specificity and avoid the challenges faced by non-specific TGF-ß inhibitors. These findings characterize avß8 as a novel and potent immunotherapy drug for further clinical investigation.
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References
Batlle E, Massagué J. Transforming growth factor-ß signaling in immunity and cancer. Immunity. 2019;50(4):924–940.
Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFß drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018;554(7693):538–543.
Mariathasan S, Turley SJ, Nickles D, et al. TGFß attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018;554(7693):544–548.
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