The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies - physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-adrenergic receptor knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intra-tumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of PD-1, in addition to an elevated effector CD8+ T cell to CD4+ regulatory T cell ratio (IFN-γ+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-adrenergic receptor signaling to regulate the immune status of the tumor microenvironment and supports the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy.
http://ift.tt/2wlgvOQ
Πέμπτη 17 Αυγούστου 2017
{beta}-adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy
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