Sex parity in stimulation of murine lymphocyte trafficking in response to fever-range systemic thermal therapy

Abstract

Murine preclinical studies established that hyperthermia regimens stimulate immunity by mobilizing lymphocyte homing to lymph nodes and tumors. Enhanced lymphocyte trafficking during fever-range systemic thermal therapy (FR-STT) is driven by interleukin-6 (IL-6) upregulation of intercellular adhesion molecule-1 (ICAM-1) on blood vessels in lymph nodes and tumors. However, since hyperthermia regulation of lymphocyte homing was only evaluated in female mice, the response of male mice remains unknown. Here, we investigated the potential sex bias in response to FR-STT by assessing the function of lymph node high endothelial venules (HEV) that are a thermally-responsive vascular site. Although it was feasible to elevate core temperatures to 39.5 ± 0.5 °C for 6 h in female and male mice, males were significantly less tolerant to FR-STT. Under normothermic controls, there was no difference between females and males in baseline intranodal (a) HEV frequency, (b) HEV area, (c) IL-6 concentration, and (d) lymphocyte trafficking. FR-STT further induced similar increases in ICAM-1 expression on HEV and lymphocyte trafficking in lymph nodes in both sexes. While FR-STT did not alter intranodal IL-6 concentrations, findings that IL-6 was higher in lymph nodes than the circulation in both sexes suggest that local IL-6 is responsible for systemic vascular responses to FR-STT. Collectively, these data demonstrate that despite sexual dimorphism in thermal regulation in mice, there was no evidence of a sex bias for lymphocyte homing at checkpoint HEV. Thus, hyperthermia treatment is predicted to be equally effective in boosting immunity in male and female mice when combined with immunotherapy.

Keywords: Hyperthermia; cancer immunotherapy; fever-range thermal therapy; lymphocyte trafficking; sex bias.