Sex-biased adaptive immune regulation in cancer development and therapy
Johanna M. Schafer,
Tong Xiao,
Hyunwoo Kwon,
Katharine Collier,
Yuzhou Chang,
Hany Abdel-Hafiz,
Chelsea Bolyard,
Dongjun Chung,
Yuanquan Yang,
Debasish Sundi,
Qin Ma,
Dan Theodorescu,
Xue Li,
Zihai Li
Affiliations
Johanna M. Schafer
Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
Tong Xiao
Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
Hyunwoo Kwon
Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA; Medical Scientist Training Program, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
Katharine Collier
Division of Medical Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
Yuzhou Chang
Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA; Department of Biomedical Informatics, the Ohio State University, Columbus, OH 43210, USA
Hany Abdel-Hafiz
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Chelsea Bolyard
Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
Dongjun Chung
Department of Biomedical Informatics, the Ohio State University, Columbus, OH 43210, USA
Yuanquan Yang
Division of Medical Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
Debasish Sundi
Department of Urology, the Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
Qin Ma
Department of Biomedical Informatics, the Ohio State University, Columbus, OH 43210, USA
Dan Theodorescu
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Xue Li
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Zihai Li
Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA; Corresponding author
Summary: The cancer research field is finally starting to unravel the mystery behind why males have a higher incidence and mortality rate than females for nearly all cancer types of the non-reproductive systems. Here, we explain how sex – specifically sex chromosomes and sex hormones – drives differential adaptive immunity across immune-related disease states including cancer, and why males are consequently more predisposed to tumor development. We highlight emerging data on the roles of cell-intrinsic androgen receptors in driving CD8+ T cell dysfunction or exhaustion in the tumor microenvironment and summarize ongoing clinical efforts to determine the impact of androgen blockade on cancer immunotherapy. Finally, we outline a framework for future research in cancer biology and immuno-oncology, underscoring the importance of a holistic research approach to understanding the mechanisms of sex dimorphisms in cancer, so sex will be considered as an imperative factor for guiding treatment decisions in the future.
