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.

Defining the incidence of cutaneous squamous cell carcinoma in coastal NSW Australia

“…It may be that there are molecular influences determining some of this observed difference. 12 The relative risk of developing a primary cSCC was greatest in the southern and coastal regions of the study area for those over 60 years of age. This was not the case for those 40-60 years, where further inland saw the greatest relative risk.…”

“…This sex disparity has long been thought to reflect both leisure and work habits of men favouring prolonged UV exposure throughout early life. It may be that there are molecular influences determining some of this observed difference 12 …”

A tEMTing target? Clinical and experimental evidence for epithelial-mesenchymal transition in the progression of cutaneous squamous cell carcinoma (a scoping systematic review)

“…The increased incidence is often attributed life-style choices. However, more recent research suggests an underlying biological cause [ 139 , 142 ]. Some scarce evidence infers a role of hormonal signalling in modulating EMT in cSCC.…”

Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma

“…Further, due to histopathologic tumor percentage estimation and other quality control measures, in this study only 1 female sample was sequenced. Others have highlighted that age, male sex and immunosuppression are among risk factors for metastasis [32] while another study reports sex determined immunological mechanisms as a determinant of the development of metastasis in cSCC [33]. Two patients were immunocompromised; one patient was on long-term azathioprine for rheumatoid arthritis and the other was on a combination of cyclophosphamide and tacrolimus following solid organ transplantation.…”