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Serum Complement Factor H: A Marker for Progression and Outcome Prediction Towards Immunotherapy in Cutaneous Squamous Cell Carcinoma
by
, , , , , , , and
Glenn Geidel
1,2,†
,
Laura Adam
1,†,
Sabrina Bänsch
1,
Nathan Fekade
1,
Benjamin Deitert
1,2,
Alessandra Rünger
1,2,
Julian Kött
1,2,
Tim Zell
1,2,
Isabel Heidrich
1,2,3,
Daniel J. Smit
2,3,
Klaus Pantel
2,3,
Stefan W. Schneider
1,2 and
Christoffer Gebhardt
1,2,*
1
Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
2
Fleur Hiege Center for Skin Cancer Research, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
3
Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2025, 17(13), 2162; https://doi.org/10.3390/cancers17132162
Submission received: 19 May 2025
/
Revised: 25 June 2025
/
Accepted: 26 June 2025
/
Published: 26 June 2025
(This article belongs to the Section Cancer Causes, Screening and Diagnosis)
Simple Summary
Cutaneous squamous cell carcinoma is a common form of skin cancer that is usually curable with surgery. However, some tumors grow aggressively, spread, or become unresectable. In these cases, systemic therapies like immunotherapy may be required. Predicting which tumors will behave aggressively or respond to treatment remains challenging. In this study, we measured the blood levels of a protein called complement factor H in patients with different stages of cutaneous squamous cell carcinoma. We found that higher levels of complement factor H were associated with more advanced disease and poorer responses to immunotherapy. Our results suggest that complement factor H may serve as a simple blood-based marker to identify patients with aggressive cutaneous squamous cell carcinoma earlier. It could also aid in predicting how patients might respond to immunotherapy. These insights may help clinicians individualize surveillance and treatment strategies for this disease.
Abstract
Background/Objectives: Tumor-immune system interactions shape the progression of cutaneous squamous cell carcinoma (cSCC). Serum biomarkers for risk stratification remain limited. Complement factor H (CFH) regulates the alternative complement pathway. It has been linked to immunosuppression and cSCC development in tissue-based studies. We investigated whether serum CFH is associated with tumor aggressiveness and may help predict immunotherapy outcomes in advanced cSCC. Methods: In this retrospective, single-center study, pre-treatment serum CFH levels were measured in 104 cSCC patients (62 high-risk and 42 advanced) using ELISA. Associations with clinical characteristics, disease stage, and response to cemiplimab were analyzed. Subgroup comparisons considered immune status and inflammatory comorbidities. Results: Advanced cSCC patients had significantly higher CFH levels than high-risk patients (OR 0.13, p = 0.026), independent of tumor diameter or invasion depth. Among advanced cSCC cases, lower baseline CFH was associated with more prolonged progression-free survival (median 19.8 vs. 3.07 months, p = 0.029; HR 0.29, p = 0.014), independent of covariates including immunosuppression. CFH levels during therapy did not predict treatment response. ROC analysis showed moderate discriminatory ability with CFH alone (AUC 0.625), which improved when combined with clinical variables in a multivariable risk model (AUC 0.767). Conclusions: Serum CFH is an independent predictor of cemiplimab response and reflects biological aggressiveness in cSCC beyond conventional high-risk features. These findings support the use of CFH in clinical risk models and warrant external validation in multicenter cohorts.
