There is significant variability in the expression of cancer-related fatigue. Understanding the factors that account for this variation provide insight into the underlying mechanisms. One important, but often overlooked, variable is biological sex. While a few clinical studies have indicated that female patients report higher levels of fatigue, these studies are subject to potential socio-culture reporting biases. Only a limited number of preclinical studies have considered sex differences in animal model of fatigue and few have simultaneously considered both disease- and treatment-related factors. The present series of studies was initiated to address the current knowledge gap on the importance of sex differences in cancer-related fatigue. We selected a murine model of human papilloma virus-positive head and neck cancer based on heterotypic injection of the mEERL95 cell line that grows in both male and female mice and responds to a regimen of cisplatin plus irradiation. We also tested the impact of immunotherapy treatment targeting PD1. Voluntary wheel running was used to evaluate fatigue-like behavior. Male mice grew larger tumors than did female mice and showed more severe fatigue-like behavior. We confirmed that the tumor increased the expression of inflammatory cytokines in the liver, but no sex differences were observed. As a trend toward elevated Cd3 mRNA was observed in female mice, we tested the importance of T cells using female Rag2-/- mice. The Rag2-/- female mice had accelerated tumor growth and more severe fatigue-like behavior. In response to cisplatin alone non-tumor-bearing female mice showed a slower recovery of wheel running activity compared to males. However, in response to chemoradiation and anti-PD1 neutralizing antibody, tumor-bearing female mice showed a better tumor response to therapy than male mice, but no significant sex differences were observed for wheel running. These findings point to different mechanisms underlying tumor- and treatment-induced behavioral fatigue and indicate that the sex factor can intervene to modulate the expression of fatigue-like behavior in particular circumstances.

癌症相关疲劳的表现存在显着差异。了解造成这种变化的因素可以深入了解潜在的机制。一个重要但经常被忽视的变量是生物性别。虽然一些临床研究表明女性患者报告的疲劳程度较高，但这些研究可能存在潜在的社会文化报告偏差。只有有限数量的临床前研究考虑了疲劳动物模型中的性别差异，并且很少同时考虑疾病和治疗相关因素。本系列研究旨在解决目前关于性别差异在癌症相关疲劳中的重要性的知识差距。我们基于异型注射 mEERL95 细胞系，选择了人乳头状瘤病毒阳性头颈癌小鼠模型，该细胞系在雄性和雌性小鼠中均生长，并对顺铂加照射方案有反应。我们还测试了针对 PD1 的免疫疗法的影响。自愿车轮行驶用于评估疲劳样行为。雄性小鼠比雌性小鼠长出更大的肿瘤，并表现出更严重的疲劳样行为。我们证实肿瘤增加了肝脏中炎症细胞因子的表达，但没有观察到性别差异。由于在雌性小鼠中观察到Cd3 mRNA 升高的趋势，我们使用雌性Rag2 -/- 小鼠测试了 T 细胞的重要性。 Rag2-/-雌性小鼠肿瘤生长加速，疲劳样行为更严重。作为对单独顺铂的反应，与雄性小鼠相比，非荷瘤雌性小鼠的跑轮活动恢复较慢。 然而，针对放化疗和抗PD1中和抗体，荷瘤雌性小鼠比雄性小鼠表现出更好的肿瘤治疗反应，但在轮跑方面没有观察到显着的性别差异。这些发现指出了肿瘤和治疗引起的行为疲劳的不同机制，并表明性别因素可以干预以调节特定情况下类疲劳行为的表达。