Female Immunity Protects from Cutaneous Squamous Cell Carcinoma

Area of Science:

• Oncology
• Immunology
• Dermatology

Background:

• Cancer incidence and mortality rates are higher in males.
• Existing research suggests men face higher risks for epithelial cancers due to increased carcinogen exposure and accumulated damage.
• The mutational and transcriptomic landscape of cancer exhibits significant sex-based differences.

Purpose of the Study:

• To investigate the clinical and molecular sexual disparities in primary cutaneous squamous cell carcinoma (cSCC).
• To explore the role of sex in cSCC aggressiveness and immune response.
• To determine if female immunity provides a protective advantage in cSCC development and progression.

Main Methods:

• Analysis of clinical and molecular data from immunocompetent and immunosuppressed patients with primary and advanced-stage cSCC.
• Experimental models using FVB/N mice exposed to equal doses of DMBA (7,12-dimethylbenz[a]anthracene).
• Whole-exome, bulk, and single-cell RNA sequencing of human keratinocytes and mouse models.

Main Results:

• Cutaneous squamous cell carcinoma (cSCC) is more aggressive in males, while immunocompetent females develop milder forms later in life.
• Male mice exposed to carcinogens developed more aggressive, metastatic cSCC compared to females.
• Female mice and human keratinocytes demonstrated enhanced cancer immune-related expression pathways and T-cell infiltration, a response diminished in immunosuppressed models.
• Males exhibited increased mitosis and proliferation rates in response to carcinogens.
• A compromised immune system specifically led to high-risk, aggressive cSCC in women.

Conclusions:

• The immune response in cSCC is significantly sex-biased.
• Female immunity provides a demonstrably greater protective effect against cSCC compared to male immunity.
• Understanding these sex-based immune differences is crucial for developing targeted cancer therapies.