Female immunity protects from cutaneous squamous cell carcinoma
Female immunity protects from cutaneous squamous cell carcinoma
Abstract PurposeCancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women are more protected from aggressive cutaneous squamous cell carcinoma (cSCC) due to strong immune activation. MethodsWe explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients (N= 738, N=160) with carcinoma cSCC, in FVB/N mice exposed to equal doses of DMBA, and in human keratinocytes by whole exome sequencing, bulk and single cell RNA sequencing. ResultsWe show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test if sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T cell infiltration independently of mutations. In contrast, males increase the rate of mitoses and proliferation in response to carcinogen. Human female skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at ultraviolet radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. ConclusionsThis work shows the immune response is sex biased in cSCC, and highlights female immunity offers greater protection than male immunity. Translational relevanceSex bias affects cancer incidence, mortality and therapy response; and the molecular landscape of cancer differs by sex. However, it is not known if the sex discrepancy is due to a difference in behaviour and exposure to carcinogens, or due to sex-linked susceptibility. This work reveals men are inherently more susceptible to cutaneous aggressive squamous cell carcinoma, in contrast to women who activate stronger immune responses when challenged with the same carcinogens. The loss of immunity particularly affects women.Personalised medicine approaches stratify cancer patients by genotype; however, to date, the potential for cancer stratification, prevention strategies and therapy by sex and immune competency has not been explored. These data indicate men require targeted prevention programs and increased monitoring. Furthermore, we provide a rationale to prioritise men and immunosuppressed women for adjuvant therapy and immunotherapy.
Earnshaw Charles、Ra Amelle、Akhras Victoria、Green Ruth、Jamieson Lynne、Lear John、Motta Luisa、Oudit Deemesh、Furney Simon J、Hu Yuan、Craig Sarah、Budden Timothy、Caul¨an Carlos、Vir¨?s Amaya、Gurung Shilpa、Gaudy-Marqueste Caroline、Shenjere Patrick
Skin Cancer and Ageing Lab, Cancer Research UK Manchester Institute, The University of Manchester||National Institute for Health Research Manchester Biomedical Research CentreDepartment of Dermatology, St. George?ˉs NHS Foundation TrustDepartment of Dermatology, St. George?ˉs NHS Foundation TrustDepartment of Histopathology, Salford Royal NHS Foundation Trust, The University of ManchesterDepartment of Histopathology, Salford Royal NHS Foundation Trust, The University of ManchesterDepartment of Dermatology, Salford Royal NHS Foundation Trust, The University of ManchesterDepartment of Histopathology, Salford Royal NHS Foundation Trust, The University of ManchesterDepartment of Plastic and Reconstructive Surgery, The Christie Hospital NHS Foundation TrustGenomic Oncology Research Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland||Centre for Systems Medicine, Royal College of Surgeons in Ireland DublinDepartment of Otolaryngology, Head and Neck Surgery, University of Arizona||University of Arizona Cancer Center, University of ArizonaSkin Cancer and Ageing Lab, Cancer Research UK Manchester Institute, The University of Manchester||National Institute for Health Research Manchester Biomedical Research CentreSkin Cancer and Ageing Lab, Cancer Research UK Manchester Institute, The University of Manchester||National Institute for Health Research Manchester Biomedical Research CentreAix Marseille Univ, APHM, CRCM Inserm U1068, CNRS U7258, CHU Timone, Dermatology and Skin Cancer Department||Department of Otolaryngology, Head and Neck Surgery, University of ArizonaSkin Cancer and Ageing Lab, Cancer Research UK Manchester Institute, The University of Manchester||National Institute for Health Research Manchester Biomedical Research CentreSkin Cancer and Ageing Lab, Cancer Research UK Manchester Institute, The University of Manchester||National Institute for Health Research Manchester Biomedical Research CentreAix Marseille Univ, APHM, CRCM Inserm U1068, CNRS U7258, CHU Timone, Dermatology and Skin Cancer DepartmentDepartment of Histopathology, The Christie Hospital NHS Foundation Trust
肿瘤学皮肤病学、性病学基础医学
cancer sex biascutaneous SCCcancer immunity activationnon-melanoma cancercancer and immunosuppression
Earnshaw Charles,Ra Amelle,Akhras Victoria,Green Ruth,Jamieson Lynne,Lear John,Motta Luisa,Oudit Deemesh,Furney Simon J,Hu Yuan,Craig Sarah,Budden Timothy,Caul¨an Carlos,Vir¨?s Amaya,Gurung Shilpa,Gaudy-Marqueste Caroline,Shenjere Patrick.Female immunity protects from cutaneous squamous cell carcinoma[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2021.01.28.428489.点此复制
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