Abstract
Sex differences are present across multiple non-reproductive organ cancers, with male individuals generally experiencing higher incidence of cancer with poorer outcomes. Although some mechanisms underlying these differences are emerging, the immunological basis is not well understood. Observations from clinical trials also suggest a sex bias in conventional immunotherapies with male individuals experiencing a more favourable response and female individuals experiencing more severe adverse events to immune checkpoint blockade. In this Perspective article, we summarize the major biological hallmarks underlying sex bias in immuno-oncology. We focus on signalling from sex hormones and chromosome-encoded gene products, along with sex hormone-independent and chromosome-independent epigenetic mechanisms in tumour and immune cells such as myeloid cells and T cells. Finally, we highlight opportunities for future studies on sex differences that integrate sex hormones and chromosomes and other emerging cancer hallmarks such as ageing and the microbiome to provide a more comprehensive view of how sex differences underlie the response in cancer that can be leveraged for more effective immuno-oncology approaches.
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Acknowledgements
This work is supported by the Pelotonia Institute for Immuno-Oncology (to Z.L.), the American Brain Tumour Association (to J.L.), the Cleveland Clinic (to J.L. and J.D.L.), the Case Comprehensive Cancer Center (to J.D.L.), the US National Institutes of Health grants P01 CA245705 (to J.D.L.), P01 CA278732 (to Z.L.), R01 CA262069 (to Z.L.), R35 NS127083 (to J.D.L.), R01 AG084250 (to J.D.L.) and T32 2T32CA09223-16A1 (to T.D.G.), and the Pelotonia Graduate Fellowship Program from The Ohio State University Comprehensive Cancer Center-James (to T.X.).
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Glossary
- All-cause mortality
-
The death rate from all causes of death for a population within a specific time period.
- Castration
-
A medical procedure that involves the removal or suppression of the testes in males.
- Four-core genotype (FCG) mouse model
-
A mouse strain that has four possible combinations of sex chromosome complement and gonadal sex — XX gonadal males (XXM), XY gonadal males (XYM), XX gonadal females (XXF) and XY gonadal females (XYF) — used to investigate the influence of sex chromosomes and gonadal hormones separately.
- Graft-versus-leukaemia effect
-
The ability of donor immune cells to eliminate host leukaemic cells after allogeneic haematopoietic stem cell transplantation.
- Hypogonadism
-
A condition in both males and females in which the body’s sex glands produce little or no sex hormones.
- Pharmacodynamic
-
The biochemical and physiological effects of the foreign chemicals on the body.
- Pharmacokinetic
-
The dynamic changes of foreign chemicals in the body.
- Progenitor-exhausted CD8+ T cells
-
A subpopulation of CD8+ tumour-infiltrating lymphocytes that retain polyfunctionality, persist long term and differentiate into ‘terminally exhausted’ progenies.
- Regulatory T (Treg) cells
-
A subset of CD4+ T lymphocytes that are defined by FOXP3 expression and suppress the immune system to prevent autoimmune reactions.
- T follicular helper cell
-
A subset of CD4+ T lymphocytes that have a key role in regulating B cell responses and antibody production within lymphoid follicles during the immune response.
- T helper 1 (TH1) cells
-
A subset of CD4+ T lymphocytes that promote cell-mediated immune responses and is required for host defence against intracellular viral and bacterial pathogens.
- T helper 17 (TH17) cells
-
A subset of pro-inflammatory CD4+ T lymphocytes defined by their production of IL-17 and have an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces.
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Xiao, T., Lee, J., Gauntner, T.D. et al. Hallmarks of sex bias in immuno-oncology: mechanisms and therapeutic implications. Nat Rev Cancer 24, 338–355 (2024). https://doi.org/10.1038/s41568-024-00680-z
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DOI: https://doi.org/10.1038/s41568-024-00680-z
