Breakthrough finding reveals how male sex hormones contribute to cancer-related sex bias

Patients with cancers stemming from non-reproductive organs, such as bladder and liver cancer, have striking discrepancies in incidence, progression, response to treatment and survival outcomes depending on their sex. In almost all cases, male patients have worse prognoses and outcomes. This phenomenon has puzzled the scientific community for decades.

A study published today in Science Immunology and led by researchers in the Pelotonia Institute for Immuno-Oncology (PIIO) at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) examined the differences in intratumoral immune responses between male and female cancers of non-reproductive origin.

The focus of this research was the T cell immune response to malignancy, a key determinator of outcomes in cancer, and an important target that has contributed to the renaissance of cancer immunotherapy seen in recent years. The study reported a landmark finding that describes how male sex hormones contribute to cancer-related sex bias via the modulation of CD8⁺ T cells-;a population of cells often referred to as cancer "killer" cells, which mediate adaptive immunity and are critical for mounting an anti-tumor response.

Collectively, these findings highlight androgen-mediated promotion of CD8⁺ T cell dysfunction in cancer and suggest broader implications for therapeutic development to address sex disparities in health and disease."

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Dr. Zihai Li, study's senior corresponding author, cancer immunologist, medical oncologist and founding director of the PIIO at OSUCCC – James

Androgens are sex hormones more highly present in males. This study revealed that CD8⁺ T cells from cancers in male subjects, including human patients and mice, are more likely to have characteristics of a weakened anti-tumor immune function, also known as "exhausted" T cells. Androgen signaling promotes the progenitor exhausted CD8⁺ T cell phenotype via modulating expression of TCF1, a master regulator of CD8⁺ T cell function.

"Androgen-mediated promotion of CD8⁺ T cell dysfunction results in faster tumor growth and worsened outcomes, and targeting of this signaling cascade holds a crucial key to improving current cancer immunotherapies," said Li, who is also a professor in the Ohio State College of Medicine.

This work was made possible because of the unique collaborations happening in Ohio State's Pelotonia Institute for Immuno-Oncology. Founded in 2019, the PIIO is a comprehensive bench-to-bedside research initiative focused on harnessing the body's immune system to fight cancer at all levels -; from prevention to treatment and survivorship. The institute is centered on systems and translational immuno-oncology and supported by immune monitoring and discovery as well as immuno-informatics.

The PIIO was established through a $102 million pledge from OSUCCC – James and Pelotonia. Founded in 2008, Pelotonia was established with the objective to fund innovative cancer research, and has raised over $236 million for cancer research.

Additional financial support for the study came from the National Institutes of Health, Prostate Cancer Foundation, Canadian Institutes of Health Research and Hollings Cancer Center.