Immune and tumor-intrinsic signatures are associated with resistance and response to PD-1 blockade in cutaneous squamous cell carcinoma
6 affiliations
- 1Department of Dermatology, Ruhr-University Bochum, Johannes Wesling Medical Center, Campus Minden, Hans Nolte Str. 1, 32429 Minden, Germany
- 2Department of Dermatology, Allergy and Venerology, Hannover Medical School, Hannover, Germany
- 3Department of Dermatology, Klinikum Bremerhaven, Bremerhaven, Germany
- 4Department of Dermatology, Elbe Kliniken Buxtehude, Buxtehude, Germany
- 5Department of Dermatology, St. Josef-Hospital Bochum, Ruhr-University Bochum, Bochum, Germany
- 6Department of Dermatology, Dortmund Hospital gGmbH, University Witten, Herdecke, Germany
Abstract
Background: Anti-PD-1 therapy has significantly improved clinical outcomes in patients with advanced cutaneous squamous cell carcinoma (cSCC); however, approximately half of patients fail to respond. This study aimed to investigate molecular mechanisms underlying therapeutic resistance and to identify predictive biomarkers.
Methods: Whole transcriptome profiling was performed using HTG EdgeSeq technology on pre-treatment cSCC samples. Clinical data and treatment outcomes were correlated with gene expression profiles, and differentially expressed genes (DEGs) were analyzed in relation to response. Moreover, promising targets were further analyzed at the protein level via immunofluorescence and immunohistochemistry.
Results: Tumors from patients achieving disease control showed a distinct immune-active transcriptional profile characterized by interferon-associated signaling, enhanced antigen presentation pathways, and cytotoxic immune activity. Consistently, IFN-γ and cytolytic activity signatures were higher in patients with favorable clinical outcomes. CIBERSORTx-based deconvolution demonstrated marked interpatient heterogeneity, with T cells, macrophages, and NK cells representing major components of the immune infiltrate, but no major differences in overall immune cell composition between patients with early and late/no progression. Histopathological assessment revealed a tendency toward higher immune cell infiltration in patients achieving disease control. Notably, elevated gene expression of SLC7A5 and SOX2 was associated with poor response and early progression. Also, at protein level, higher SLC7A5 expression was associated with early progression, whereas SOX2 showed a more heterogeneous pattern, with particularly high expression in a subset of progressive tumors.
Conclusion: Our data provide hypothesis-generating evidence that a combination of immune-related and tumor-intrinsic novel molecular markers is associated with response to anti-PD-1 therapy in advanced cSCC, thereby identifying promising candidate biomarkers, which require validation in larger independent cohorts.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04610-w.
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BibTeX
@article{detemple2026immune,
title = {{Immune and tumor-intrinsic signatures are associated with resistance and response to PD-1 blockade in cutaneous squamous cell carcinoma}},
author = {Viola K. DeTemple and Maximilian Beikirch and Alina C. Ulama and Moritz Bergmann and Sabine Bredemeier and Vivien Schacht and Michael Sachse and Peter Mohr and Thilo Gambichler and Ralf Gutzmer and Katrin Schaper-Gerhardt},
journal = {Cancer Immunology, Immunotherapy : CII},
year = {2026},
month = oct,
doi = {10.1007/s00262-026-04610-w},
url = {https://doi.org/10.1007/s00262-026-04610-w},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immune and tumor-intrinsic signatures are associated with resistance and response to PD-1 blockade in cutaneous squamous cell carcinoma
AU - Viola K. DeTemple
AU - Maximilian Beikirch
AU - Alina C. Ulama
AU - Moritz Bergmann
AU - Sabine Bredemeier
AU - Vivien Schacht
AU - Michael Sachse
AU - Peter Mohr
AU - Thilo Gambichler
AU - Ralf Gutzmer
AU - Katrin Schaper-Gerhardt
PY - 2026
DA - 2026/10/30
JO - Cancer Immunology, Immunotherapy : CII
DO - 10.1007/s00262-026-04610-w
UR - https://doi.org/10.1007/s00262-026-04610-w
AB - Background: Anti-PD-1 therapy has significantly improved clinical outcomes in patients with advanced cutaneous squamous cell carcinoma (cSCC); however, approximately half of patients fail to respond. This study aimed to investigate molecular mechanisms underlying therapeutic resistance and to identify predictive biomarkers. Methods: Whole transcriptome profiling was performed using HTG EdgeSeq technology on pre-treatment cSCC samples. Clinical data and treatment outcomes were correlated with gene expression profiles, and differentially expressed genes (DEGs) were analyzed in relation to response. Moreover, promising targets were further analyzed at the protein level via immunofluorescence and immunohistochemistry. Results: Tumors from patients achieving disease control showed a distinct immune-active transcriptional profile characterized by interferon-associated signaling, enhanced antigen presentation pathways, and cytotoxic immune activity. Consistently, IFN-γ and cytolytic activity signatures were higher in patients with favorable clinical outcomes. CIBERSORTx-based deconvolution demonstrated marked interpatient heterogeneity, with T cells, macrophages, and NK cells representing major components of the immune infiltrate, but no major differences in overall immune cell composition between patients with early and late/no progression. Histopathological assessment revealed a tendency toward higher immune cell infiltration in patients achieving disease control. Notably, elevated gene expression of SLC7A5 and SOX2 was associated with poor response and early progression. Also, at protein level, higher SLC7A5 expression was associated with early progression, whereas SOX2 showed a more heterogeneous pattern, with particularly high expression in a subset of progressive tumors. Conclusion: Our data provide hypothesis-generating evidence that a combination of immune-related and tumor-intrinsic novel molecular markers is associated with response to anti-PD-1 therapy in advanced cSCC, thereby identifying promising candidate biomarkers, which require validation in larger independent cohorts. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04610-w.
SN - 0340-7004
SN - 1432-0851
ER -