Beta-adrenergic mediated suppression of T cell chemotaxis by cancers

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ABSTRACT Tumor growth induces local and systemic immunosuppressive effects that diminish immune cell infiltrationoftumors,therebylimitingtheefficacyofTcell-basedimmunotherapies.Wepreviously demonstrated that restoration of interferon signaling and downstream expression of CXCR3 cognate chemokines is sufficient to restore T cell infiltration of tumors. However, the mechanisms that modulate chemokine production and T cell infiltration in tumors remain poorly defined. Recent studies have reported that mice maintained at standard vivarium temperatures (ST conditions, ~24°C) experience chronic cold stress and induction of -adrenergic signaling, including induction of high levels of circulating norepinephrine (NE), relative to mice maintained in thermoneutral (TN) conditions (28-30°C). Significantly, tumors grow more rapidly in ST- conditioned mice, concurrent with reduced CD8 infiltration and chemokine production. Thus, tumors in ST mice immunologically resemble patient-derived samples (NE replete and lacking chemokine and T cell infiltrates), suggesting that stress-induced signaling pathways may play a major role in limiting immune responses to tumors. We propose that -adrenergic signaling suppresses interferon and interferon-inducible chemokine production (including CXCR3-cognate chemokines CXCL9 and CXCL10) in the tumor microenvironment, thereby limiting CXCR3+CD8 T cell infiltration and immune-mediated tumor rejection. By extension, blocking -adrenergic signaling may induce or restore interferon-inducible chemokine production and CXCR3+ T cell infiltration in tumors. In this exploratory/developmental study, we will 1) investigate the role of - adrenergic signaling in regulation of chemokine production and T cell trafficking to the melanoma microenvironment; and 2) assess the impact of -adrenergic signaling on T cell-based therapies for cancer. These studies will inform future R01-scale investigations of the specific molecular and cellular mechanisms of action in stress-mediated changes in the tumor microenvironment, and provide a conceptual basis to translate these preclinical studies into clinical Phase 0/1 trials that combine -blockers and cancer immunotherapy for the purpose of enhancing T cell infiltration and anti-tumor efficacy.