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Updated: Feb 1, 2026
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Single-cell spatial transcriptomics uncovers niches that govern response to PD-1/PD-L1 blockade in cutaneous squamous
Maxwell Y Lee1, Alistaire R Sherman1, Luis Martinez Ramirez2
1Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Palo Alto, California, USA.
Background:
Neoadjuvant PD-1/PD-L1 blockade yields robust efficacy in advanced cutaneous squamous cell carcinoma (cSCC), yet many patients fail to achieve a complete or major pathologic response. The reasons why some patients experience response but others do not are unclear.
Methods:
We profiled cSCC specimens before, after 1 dose, and after 3-4 doses of PD-1/PD-L1 blockade to uncover resistance mechanisms and predict therapeutic response. In total, 27 patients across three cohorts, including two phase II trials, were studied. We created 1.7 mm tissue-core microarrays and performed single-cell spatial transcriptomics, including spatial clustering, gene-set enrichment, and spatial correlation analyses.
Results:
After profiling all samples, six distinct spatial niches emerged, each differentially enriched in responders versus non-responders. A high antigen presentation niche, B/plasma cell enriched niche, and inflammatory keratinocyte niche were more frequent in responders, whereas proliferative keratinocyte, low antigen presentation myeloid, and fibroblast-rich epithelial-mesenchymal transition niches prevailed in non-responders. Notably, spatial niche profiling on pretreatment samples outperformed PD-L1 status in predicting pathologic response. Each niche displayed unique gene coexpression modules, suggesting niche-specific resistance mechanisms. Individual tumor analyses revealed varied immune evasion strategies, including defective interferon-induced antigen presentation, immunosuppressive myeloid environments, and epithelial-mesenchymal transition.
Conclusions:
Our single-cell spatial transcriptomic approach identifies six spatial niches that predict immunotherapy response better than PD-L1 status using only 1.7 mm tissue cores and may inform the development of biomarkers. Our results further underscore the heterogeneity of resistance mechanisms among cSCC patients, highlighting the need for tailored therapeutic strategies.
Insights
Investigating cutaneous squamous cell carcinoma (cSCC) reveals six distinct spatial niches that predict immunotherapy response. This approach using spatial transcriptomics offers better prediction than PD-L1 status and highlights diverse resistance mechanisms.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Neoadjuvant PD-1/PD-L1 blockade shows efficacy in advanced cutaneous squamous cell carcinoma (cSCC).
- However, many patients do not achieve a complete response, and reasons for this are unclear.
- Understanding resistance mechanisms is crucial for improving treatment outcomes.
Purpose of the Study:
- To uncover resistance mechanisms to PD-1/PD-L1 blockade in cSCC.
- To identify biomarkers that predict therapeutic response.
- To explore the heterogeneity of immune evasion strategies in cSCC.
Main Methods:
- Profiling of cSCC specimens before and after PD-1/PD-L1 blockade using single-cell spatial transcriptomics.
- Analysis of 27 patients across three cohorts, including two phase II trials.
- Utilizing tissue-core microarrays, spatial clustering, gene-set enrichment, and spatial correlation analyses.
Main Results:
- Six distinct spatial niches were identified, with differential enrichment in responders versus non-responders.
- Responders showed higher frequencies of antigen presentation, B/plasma cell, and inflammatory keratinocyte niches.
- Non-responders were characterized by proliferative keratinocyte, low antigen presentation myeloid, and epithelial-mesenchymal transition niches.
- Spatial niche profiling outperformed PD-L1 status in predicting pathologic response.
- Niches exhibited unique gene coexpression modules, suggesting niche-specific resistance mechanisms.
- Observed immune evasion strategies included defective antigen presentation, immunosuppressive myeloid environments, and epithelial-mesenchymal transition.
Conclusions:
- Single-cell spatial transcriptomics identified six spatial niches that predict immunotherapy response in cSCC.
- This approach, using small tissue cores, is more predictive than PD-L1 status and may aid biomarker development.
- Results highlight the heterogeneity of resistance mechanisms, emphasizing the need for tailored therapeutic strategies in cSCC.
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