Sex differences in the behavioral and immune responses of mice to tumor growth and cancer therapy

• Published in: Brain, behavior, and immunity behavior, and immunity, 2021-11, Vol.98, p.161-172
• Main Authors: Vichaya, Elisabeth G., Ford, Bianca G., Moltenkine, Jessica M., Taniguchi, Cullen M., Phillip West, A., Dantzer, Robert
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cancer therapy; Fatigue; Female; Head and Neck Neoplasms; Humans; Immunity; Inflammation; Male; Mice; Mice, Inbred C57BL; Motor Activity; Sex Characteristics; Sex differences
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2021.08.225

•Sex differences in animal models of fatigue are rarely taken into consideration.•Sex differences were assessed in a murine model of HPV-related head and neck cancer.•Male mice grew larger tumors than females and showed more fatigue measured by reduced wheel running.•There was no sex difference in running wheel performance in response to cancer therapy.•There was no sex difference in liver inflammatory response to the tumor and its treatment. 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