Skin Cancer and Ageing Lab, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom.
NIHR Manchester Biomedical Research Centre, Manchester, United Kingdom.
Clin Cancer Res. 2021 Jun 1;27(11):3215-3223. doi: 10.1158/1078-0432.CCR-20-4261. Epub 2021 Apr 1.
Cancer 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 present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation.
We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC ( = 738, = 160), advanced-stage cSCC ( = 63, = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing.
We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women.
This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.
癌症易感性和死亡率在男性中更高，癌症的突变和转录组景观因性别而异。目前的假设是，男性患上皮癌的风险更高，因为他们比女性暴露于更多的致癌物，并积累更多的损伤。我们提供的数据表明，女性表现出侵袭性较低的原发性皮肤鳞状细胞癌（cSCC）和早期强烈的免疫激活。
我们探索了免疫功能正常和免疫抑制的原发性 cSCC 患者（=738，=160）、晚期 cSCC 患者（=63，=20）以及接受等量 DMBA 暴露的 FVB/N 小鼠以及人类角质形成细胞的临床和分子性别差异，进行了全外显子、批量和单细胞 RNA 测序。
我们表明 cSCC 在男性中更为侵袭性，免疫功能正常的女性在晚年发展为轻度 cSCC。为了测试性别是否导致差异，我们使雄性和雌性小鼠接受等量的致癌物，发现雄性比雌性表现出更具侵袭性和转移性的 cSCC。至关重要的是，女性独立于突变激活癌症免疫相关表达途径和 CD4 和 CD8 T 细胞浸润，这种反应在泼尼松龙治疗的动物中不存在。相比之下，男性在受到致癌物的影响时会增加有丝分裂和增殖的速度。女性的皮肤和角质形成细胞也在紫外线损伤部位激活免疫-抗癌途径和免疫细胞。至关重要的是，受损的免疫系统会导致女性特有的高危、侵袭性 cSCC。
这项工作表明，免疫反应在 cSCC 中存在性别偏见，并强调了女性免疫提供的保护作用大于男性免疫。
