Mandated Cool Housing Temperature and Adrenergic Stress reduce the efficacy of radiation and mask the “Abscopal Effect” in mouse models of cancer

Abstract

Abstract Mice used for modeling cancer and anti-tumor immunity experience increased adrenergic stress due to IACUC-mandated cool housing temperatures. We wondered if this source of stress could be impacting the efficacy of ionizing radiation and the frequency of an “abscopal” effect (in which tumors outside the field of irradiation exhibit a response, an effect linked to enhanced systemic anti-tumor immunity). When mice bearing two separate CT26 tumors were housed at a thermoneutral temperature (TT; ~30°C) and 6 Gy of radiation was delivered to one tumor, control of both the irradiated and non-irradiated tumors was much greater than that seen in both tumors of mice housed at standard cool temperature (ST; ~22°C). Moreover, when tumor bearing mice housed at ST were treated with the pan β-blocker, propranolol and radiation, we observed a significantly improved growth control of irradiated and non-irradiated tumors. These effects were lost in SCID mice, and in mice depleted of CD8+T-cells. Experiments using knockout mice specifically identified a role for the β2 adrenergic receptor in mediating these effects. Moreover, we found that intra-tumoral effector T-cells, including IFN-γ+, GzmB+, TNFα+ and T-bet+CD8+T-cells, as well as the ratio of IFNγ+CD8+T-cells to Tregs, increased while numbers of MDSC and Tregs decreased, in mice treated with β-blocker and radiation. Finally, cured mice treated with propranolol and radiation rejected local and distant rechallenges in a tumor-specific manner. In conclusion, these data suggest that adrenergic stress plays a major role in regulating the efficacy of radiation therapy. Blockade of β2 adrenergic signaling could be a useful new strategy in the radiation oncology clinic.