Abstract 3548: Loss of the type III TGF-β receptor during cancer progression generates an immunotolerant tumor microenvironment: Translational implications for TGF-β inhibition and immunotherapy biomarker development
Authors: Hanks Brent A. , Holtzhausen Alisha , Gimpel Petra , Campbell Olivia , Jamieson Rebekah , Ling Leona E. , Morse Michael A. , Lyerly H. K. , Blobe Gerard 
Published: August 2012

Abstract
We have demonstrated that the type III TGF-β receptor (TβRIII) functions to suppress cancer progression and is downregulated in several malignancies. Previous work has shown TβRIII to undergo ectodomain shedding (sTβRIII), enabling the sequestration of the soluble TGF-β ligand and the inhibition of the downstream TGF-β signaling pathway. The TGF-β cytokine is an immunosuppressive factor expressed by many tumor types to dampen the host immune response and thereby allow for tumor progression. Dendritic cells (DC) are critical antigen presenting cells involved in orchestrating antigen-specific immunity. We therefore propose that the downregulation of TβRIII during cancer development permits enhanced TGF-β signaling within local DC populations of the tumor microenvironment, allowing for evasion of the host immune response. Our data suggests that the tumor suppressor properties of TβRIII in the 4T1 murine breast cancer model are significantly diminished in immunosuppressed hosts. Indeed, loss of TβRIII allows for the progression of more immunogenic Her2/neu-expressing 4T1 tumors in vivo and suppresses Her2/neu-specific T cell responses. Importantly, the local delivery of a TGF-β antibody into 4T1-RIIIlo tumors phenocopies 4T1-RIIIhi tumors suggesting that this phenomenon is mediated by sTβRIII-dependent inhibition of soluble TGF-β in the tumor microenvironment. We have shown that 4T1-RIIIhi tumors as well as their draining lymph nodes (TDLNs) exhibit increased numbers of infiltrating CD8+ T cells, diminished FoxP3+ regulatory T cell infiltration, a TH1-polarized cytokine profile, and a mature DC phenotype relative to 4T1-RIIIlo tumors. In vitro studies have shown 4T1-RIII conditioned media to inhibit TGF-β signaling within DCs and to enhance their maturation. In addition, studies have revealed DC populations within 4T1-RIIIhi tumors to express reduced levels of the immunosuppressive indoleamine 2,3-dioxygenase (IDO) enzyme. Further work has demonstrated that plasmacytoid DCs (pDCs) within TDLNs upregulate IDO expression in response to TGF-β stimulation and that IDO expression is suppressed in the presence of TβRIII-expressing tumors. Indeed, we have found that melanoma patients with elevated sTβRIII plasma levels exhibit superior responses to treatment. We conclude that the loss of the TβRIII tumor suppressor during breast carcinogenesis results in enhanced paracrine TGF-β signaling within the pDC compartment of the tumor microenvironment. This work implies that TβRIII downregulation represents a novel mechanism for evading the host anti-tumor immune response. These findings further support the targeting of TGF-β as a strategy to enhance the efficacy of immunotherapeutic approaches for solid tumors and suggests that sTβRIII may represent a biomarker for immunotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3548. doi:1538-7445.AM2012-3548