Johnson Ellise M, Uppalapati Chandana K, Pascual Agnes S, Estrada Sarah I, Averitte Richard L, Leyva Kathryn J, Hull Elizabeth E
Biomedical Sciences Program, College of Graduate Studies, Midwestern University, Glendale, AZ, United States.
Department of Microbiology and Immunology, College of Graduate Studies, Midwestern University, Glendale, AZ, United States.
Front Oncol. 2022 Feb 10;12:819580. doi: 10.3389/fonc.2022.819580. eCollection 2022.
Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer with an estimated 750,000 cases diagnosed annually in the United States. Most cases are successfully treated with a simple excision procedure, but ~5% of cases metastasize and have a 5-year survival rate of 25-45%. Thus, identification of biomarkers correlated to cSCC progression may be useful in the early identification of high-risk cSCC and in the development of new therapeutic strategies. This work investigates the role of complement factor H (CFH) in the development of cSCC. CFH is a regulatory component of the complement cascade which affects cell mediated immune responses and increases in complement proteins are associated with poor outcomes in multiple cancer types. We provide evidence that sun exposure may increase levels of CFH, suggesting an immunomodulatory role for CFH early in the development of cSCC. We then document increased levels of CFH in cSCC samples, compared to adjacent normal tissue (ANT) routinely excised in a dermatology clinic which, in paired samples, received the same level of sun exposure. We also provide evidence that levels of CFH are even greater in more advanced cases of cSCC. To provide a potential link between CFH and immune modulation, we assessed immune system function by measuring interferon gamma (IFN-γ) and FOXP3 in patient samples. IFN-γ levels were unchanged in cSCC relative to ANT which is consistent with an ineffective cell-mediated immune response. FOXP3 was used to assess prevalence of regulatory T cells within the tissues, indicating either a derailed or inhibitory immune response. Our data suggest that FOXP3 levels are higher in cSCC than in ANT. Our current working model is that increased CFH downstream of sun exposure is an early event in the development of cSCC as it interferes with proper immune surveillance and decreases the effectiveness of the immune response, and creates a more immunosuppressive environment, thus promoting cSCC progression.
皮肤鳞状细胞癌（cSCC）是一种常见的皮肤癌形式，在美国每年估计有75万例被诊断出来。大多数病例通过简单的切除手术就能成功治疗，但约5%的病例会发生转移，其5年生存率为25%-45%。因此，鉴定与cSCC进展相关的生物标志物可能有助于早期识别高危cSCC以及开发新的治疗策略。这项工作研究了补体因子H（CFH）在cSCC发生发展中的作用。CFH是补体级联反应的一种调节成分，它影响细胞介导的免疫反应，多种癌症类型中补体蛋白水平升高与不良预后相关。我们提供的证据表明，阳光照射可能会增加CFH的水平，这表明CFH在cSCC发生发展早期具有免疫调节作用。然后我们记录了cSCC样本中CFH水平高于在皮肤科诊所常规切除的相邻正常组织（ANT），在配对样本中，它们接受相同程度的阳光照射。我们还提供证据表明，在更晚期的cSCC病例中CFH水平更高。为了提供CFH与免疫调节之间的潜在联系，我们通过测量患者样本中的干扰素γ（IFN-γ）和FOXP3来评估免疫系统功能。相对于ANT，cSCC中的IFN-γ水平没有变化，这与无效的细胞介导免疫反应一致。FOXP3用于评估组织内调节性T细胞的比例，表明免疫反应出现紊乱或受到抑制。我们的数据表明，cSCC中FOXP3水平高于ANT。我们目前的工作模型是，阳光照射后CFH水平升高是cSCC发生发展的早期事件，因为它干扰了正常的免疫监视，降低了免疫反应的有效性，并创造了一个更具免疫抑制性的环境，从而促进cSCC的进展。
