Role of the type III TGF-β receptor in modulating antitumor immunity during breast cancer progression.
10540 Background: We have shown that breast cancers downregulate the expression of the type III TGF-β receptor (TβRIII) tumor suppressor during tumor progression. Previous work has shown TβRIII to undergo ectodomain shedding, enabling the sequestration of the soluble TGF-β ligand and the inhibition of the TGF-β signaling pathway. The TGF-β cytokine inhibits dendritic cell (DC)-dependent antigen presentation. We hypothesize that the downregulation of TβRIII during breast tumor development permits enhanced TGF-β signaling within the local DCs of the tumor microenvironment allowing the tumor to evade the host immune response. METHODS: Our data suggest that the tumor suppressor properties of TβRIII in the 4T1 murine metastatic breast cancer model are diminished in immunosuppressed hosts. Indeed, loss of TβRIII allows for the progression of more immunogenic Her2/neu-expressing 4T1 tumors and suppresses Her2/neu-specific T cell responses. Flow cytometry and rt-PCR studies indicate that breast tumors which lack TβRIII expression exhibit reduced numbers of infiltrating CD8(+) T cells and increased regulatoy T cells (Tregs), findings which are supported by human microarray data. In addition, DCs within TβRIII(lo) tumors and their draining lymph nodes (TDLNs) express enhanced levels of the indoleamine 2,3-dioxygenase (IDO) enzyme as well as the CCL22 chemokine, which correlates with expanded local Treg populations. Studies have shown 4T1-RIII conditioned media to inhibit TGF-β signaling within DCs and to suppress the TGF-β-mediated inhibition of DC maturation. Our work is showing that DCs within the TDLNs of TβRIII(hi) tumors exhibit a more mature phenotype. RESULTS: The increased TGF-β signaling capacity of DCs residing in TβRIII(lo) tumors may allow for increased local CCL22 expression; thereby promoting Treg recruitment and allowing for CTLA-4-mediated IDO upregulation by local DCs. CONCLUSIONS: This pathway represents a novel mechanism for evading the host anti-tumor immune response, supports the targeting of TGF-β as a strategy to enhance the efficacy of immunotherapeutic approaches for solid tumors, and suggests that serum levels of soluble TβRIII may represent a useful biomarker for immunotherapy.
Hanks, BA; Campbell, OM; Lee, JD; Morse, M; Clay, TM; Lyerly, HK; Blobe, GC
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