New Targets for Immunotherapy in Male Cancer Patients: Sex Hormones

Scientists have identified new targets for immunotherapy in cancer patients. For example, male cancer patients with bladder or liver cancers progress and respond differently to treatment when compared with female patients. These are just two of the latest examples of disparities seen in many other cancers related to the sex differences of patients. Researchers have discovered why these differences arise, the hormones estrogen and testosterone, the reproductive organs and somatic cells play a significant role in influencing how the immune system works in males and females. The purpose of this analysis is to explore targeted immune therapies in patients who have non-reproductive cancers. Major differences exist between male and female patients with cancer, with males having a high incidence and progression of non-reproductive cancers compared to females. This difference does not exist for reproductive cancers. The hypothesis for this research is that immunotherapy will play a major role in treating all forms of cancer, but there are molecular characteristics that must be studied first to develop therapeutic modalities and achieve better outcomes.

A study was published in Science Immunology on April 16, 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 difference in intratumoral immune responses between cancers that were non-reproductive in males and females.

Focus of Research

The focus of this research is on the T cell immune response to the main malignant factor determining the outcome of cancer and the important goal that has contributed to the renaissance of cancer immunotherapy seen in recent years. This study presents an important finding that illustrates how male sex hormones contribute to cancer-related sex dependence through the modulation of CD8 + T cells — a number of cells called cancer "killer" cells, which mediate adaptation and are important for proliferation.

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

T Cells in Males

Androgens are sex hormones that are highly present in males than in females and hence may contribute to immune suppression in males as well as in females. Androgens include testosterone and the more potent dihydrotestosterone — triggered inhibitory co-receptors on CD8+ T cells. This function was observed in both male humans and in mice. This study reveals CD8+ T cells from cancers in male subjects, including human patients and mice, 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.

Prof. Li of the Ohio State College of Medicine had said, “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.”

This work was made possible because of the unique collaborations happening in Ohio State’s Pelotonia Institute for Immuno-Oncology. The PIIO was founded in 2019 and 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 PIIO was established through a $102 million pledge from OSUCCC – James and Pelotonia. Pelotonia was founded in 2008 and it was established with the objective to fund innovative cancer research, and has raised over $236 million for research of cancer.

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.

Other study authors include Hyunwoo Kwon, Johanna Schafer, No-Joon Song, Satoski Kaneko, Anqi Li, Tong Xiao, Anjun Ma, Carter Allen, Komal Das, Lei Zhou, Brian Riesenberg, Yuzhou Chang, Payton Weltge, Maria Velegraki, David Oh, Lawrence Fong, Qin Ma, and Debasish Sundi, as well as co-corresponding authors Drs. Xue Li (Cedars-Sinai Medical Center) and Dongjun Chung (OSUCCC – James).

Source-Medindia