C5aR1 Flagged as Biomarker in Cutaneous Squamous Cell Carcinoma

The receptor for the complement component C5a may be a useful therapeutic target for cases of cutaneous squamous cell carcinoma (cSCC), according to a new report.1 The study, published in the American Journal of Pathology, found that patients with increased expression of the receptor—C5aR1—on the tumor cell surface and in fibroblasts had a higher risk of metastatic disease and inferior disease-specific survival.

cSCC is the most common type of metastatic skin cancer, and its incidence is increasing, the authors explained. An estimated 3% to 5% of primary cSCCs metastasize, and patients with metastatic cSCC face low survival odds. A 2020 study found patients with metastatic cSCC had a 5-year survival rate of just 37.2%.2

The new report suggests the C5a-C5aRq axis might be a useful target in combination with existing therapies for cutaneous squamous cell carcinoma. | Image credit: vladimircaribb - stock.adobe.com

The authors examined C5a because it is one of several complement components that has been documented in cSCC.1 Specifically, they said it acts as a vasodilator and chemotactic factor, “and it increases vascular permeability and degranulation of most cells by attaching to the specific receptor C5aR1 on the target cells.”

C5aR1 has previously been found to be upregulated in several inflammatory and infectious diseases, as well as in cancer types like non-small cell lung cancer and gastric cancer. In those cancers, it has been associated with poor survival, they added.

The investigators wanted to better understand the role of C5aR1 in the progression and metastasis of cSCC, in part because of the current lack of molecular biomarkers for predicting metastasis of cSCC.

“There is an urgent need for predictive biomarkers for the prognosis of cSCC and for new therapeutic targets for metastatic cSCC,” lead investigator Veli-Matti Kähäri, MD, PhD, department of dermatology and FICAN West Cancer Research Laboratory at the University of Turku and Turku University Hospital in Finland, said in a press release.3

The investigators assessed C5aR1 levels by examining in vitro 3-dimensional spheroid co-culture of cSCC cells and skin fibroblasts, human cSCC xenograft tumors in severe combined immunodeficiency (SCID) mouse models, and a large set of patient-derived tumor samples of non-metastatic cSCC, metastatic cSCC, and cSCC metastases.1

“We observed that fibroblasts in the tumor microenvironment induced C5aR1 expression in cSCC cells,” Lauri Heiskanen, MD, the study's first author, said.3 “Exposure to recombinant C5a further increased the invasiveness of cSCC cells.”

Heiskanen, also of the University of Turku, said that in patient-derived cSCC samples, high expression levels of C5aR1 were linked with metastasis risk and poor survival.

“What is particularly interesting in the results of our study is how the tumor microenvironment—and especially fibroblasts in this study—affects progression of cSCC through C5aR1,” Pilvi Riihilä, MD, PhD, and Liisa Nissinen, PhD, University of Turku investigators, said in the press release.3 “It emphasizes the idea that the interplay between tumor cells and stromal cells plays an important role in cancer progression.”

The authors noted that there are currently 3 immune-oncologic antibody treatments approved for locally advanced and metastatic cSCCs that target the programmed cell death protein 1/programmed death ligand 1 pathway.1 The new report suggests the C5a-C5aRq axis might also be a useful target in combination with those existing therapies. Three anti-C5a antibodies and 1 small-molecule inhibitor of C5aR1 have already been approved for the treatment of inflammatory diseases, and those treatments might be viable options in advanced cSCC and other cancers, the authors noted. In addition to the treatment options, though, they said their results suggest assessment of C5aR1 could help clinicians better understand individual patient risk levels.

References

1. Heiskanen L, Nissinen L, Siljamäki E, et al. C5aR1 Promotes invasion, metastasis, and poor prognosis in cutaneous squamous cell carcinoma. Am J Pathol. 2025;195(6):1158-1171. doi:10.1016/j.ajpath.2025.02.004

2. Knuutila JS, Riihilä P, Kurki S, Nissinen L, Kähäri VM. Risk factors and prognosis for metastatic cutaneous squamous cell carcinoma: a cohort study. Acta Derm Venereol. 2020;100(16):adv00266. doi:10.2340/00015555-3628

3. Study links a novel biomarker with potential to predict and treat skin cancer metastasis. News release. Elsevier. May 29, 2025. Accessed June 6, 2025. https://www.elsevier.com/about/press-releases/study-links-a-novel-biomarker-with-potential-to-predict-and-treat-skin