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Published on: May 2, 2025
Expression of Programmed Cell Death Ligand in Cutaneous Squamous Cell Carcinoma and Treatment of Locally Advanced
Mary L Stevenson1, Claire Q F Wang2, Melody Abikhair1
1Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, New York, New York.
Importance:
Limited therapies are available in patients with inoperable locally advanced cutaneous squamous cell carcinoma (cSCC).
Objective:
To determine the efficacy of programmed cell death 1 receptor (PD-1) inhibitors in locally advanced cSCC.
Design, Setting, And Participants:
A single patient with locally advanced cSCC who declined surgery and radiotherapy underwent treatment with pembrolizumab, an anti-PD-1 antibody, at an academic dermatologic surgery section and cancer center. The patient was followed up for clinical and radiologic regression of cSCC. With the use of NanoString to amplify potential biomarkers, immunohistochemistry, and immunofluorescence, the ex vivo expression of PD-1 and a ligand (PD-L2) was assessed in 38 cSCC biopsy specimens from 24 patients with cSCC. Expression of PD-L1 and PD-L2 in the cSCC microenvironment was defined.
Intervention:
Pembrolizumab, 2 mg/kg every 3 weeks, for 4 cycles.
Main Outcomes And Measures:
Expression of PD-L1 and PD-L2 in the cSCC microenvironment.
Results:
In 1 patient with locally advanced cSCC who was treated with pembrolizumab, nearly complete tumor regression was observed after 4 cycles of therapy. The NanoString technology used in 38 cSCC biopsy specimens from 24 patients with cSCC (19 men and 5 women; mean [SD] age, 76.4 [12.2] years) detected increased PD-1 and PD-L2 expression in high-risk cSCC. Immunohistochemical analysis confirmed enhanced expression of PD-1 and its ligands in cSCC with perineural invasion (mean [SEM] expression, 5.06 [1.27]; P = .05), superficial cSCC (mean [SEM] expression, 3.58 [1.50]; P = .15), organ transplant-associated cSCC (mean [SEM] expression, 3.01 [0.54]; P = .005), and infiltrative cSCC (mean [SD] expression, 2.01 [0.30]; P = .006) compared with normal skin specimens. In double-label immunofluorescence staining, CD11c+, a marker of myeloid dendritic cells, colocalized with PD-L1 and PD-L2 in cSCC lesions.
Conclusions And Relevance:
The favorable treatment response combined with significant involvement of PD-1 and PD ligands in cSCC lesions suggests that PD-1 blockade may be a viable therapeutic option for locally advanced cSCC and provides rationale for further investigation in future clinical trials.
Insights
Programmed cell death 1 receptor (PD-1) inhibitors show promise for treating advanced cutaneous squamous cell carcinoma (cSCC). Pembrolizumab led to significant tumor regression in one patient, indicating PD-1 blockade is a viable therapeutic option for cSCC.
Area of Science:
- Oncology
- Immunology
- Dermatology
Background:
- Limited therapeutic options exist for patients with inoperable locally advanced cutaneous squamous cell carcinoma (cSCC).
- Programmed cell death 1 receptor (PD-1) inhibitors have emerged as a potential treatment modality in various cancers.
Observation:
- A single patient with locally advanced cSCC, who declined surgery and radiotherapy, received pembrolizumab, an anti-PD-1 antibody.
- The patient experienced nearly complete tumor regression after four cycles of pembrolizumab therapy.
- Biopsy specimens revealed increased expression of PD-1 and its ligand PD-L2 in high-risk cSCC, including cases with perineural invasion and organ transplant association.
Findings:
- Pembrolizumab treatment resulted in significant clinical and radiologic regression of locally advanced cSCC in the treated patient.
- Elevated expression of PD-1 and PD-L2 was detected in cSCC lesions compared to normal skin.
- PD-L1 and PD-L2 expression was found to be associated with specific cSCC subtypes and microenvironmental factors, including myeloid dendritic cell markers.
Implications:
- The observed treatment response suggests that PD-1 blockade, using agents like pembrolizumab, may be an effective therapeutic strategy for locally advanced cSCC.
- The findings provide a strong rationale for further clinical investigation of PD-1 inhibitors in larger patient cohorts with cSCC.
- Understanding the role of PD-1 and its ligands in the cSCC microenvironment can guide the development of targeted immunotherapies.
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