Immune-related gene expression profiling after PD-1 blockade in non–small cell lung carcinoma, head and neck squamous cell carcinoma, and melanoma
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Abstract
Abstract Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD <3%). Overall, our results support the hypothesis that identification of a preexisting and stable adaptive immune response as defined by mRNA expression pattern is reproducible and sufficient to predict clinical outcome, regardless of the type of cancer or the PD1 therapeutic antibody administered to patients. Cancer Res; 77(13); 3540–50. ©2017 AACR.
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In a human clinical trial of PD-1 checkpoint inhibitor treatment of two types of squamous cell carcinoma, high expression of TSK-specific genes ITGB1 and PLAU correlated with significantly reduced progression-free survival (p = 0.0137).
“In a human clinical trial of PD-1 checkpoint inhibitor treatment of two types of squamous cell carcinoma (Prat et al., 2017), high expression of TSK-specific genes ITGB1 and PLAU correlated with significantly reduced progression-free survival (p = 0.0137)”
From Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020) · cites this paper as Prat et al., 2017
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- Authors
- Prat, A., Navarro, A., Paré, L., Reguart, N., Galván, P., Pascual, T., Martínez, A., Nuciforo, P., Comerma, L., Alos, L., Pardo, N., Cedrés, S., Fan, C., Parker, J. S., Gaba, L., Victoria, I., Viñolas, N., Vivancos, A., Arance, A., & Felip, E.
- Affiliations
- Hospital Clínic de Barcelona (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- 1Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
- 4Medical Oncology Department, Vall d'Hebron Hospital, Barcelona, Spain.
- Vall d'Hebron Institute of Oncology (ES)
- 6Pathology Department, Hospital Clínic of Barcelona, Barcelona, Spain.
- UNC Lineberger Comprehensive Cancer Center (US)
- 2Medical Oncology Department, Hospital Clínic of Barcelona, Barcelona, Spain.
- Corresponding author
- Prat, Aleix
- ORCID
- Venue
- Cancer Research
- Published
- 2017-07-01
- Volume
- 77
- Issue
- 13
- Pages
- 3540-3550
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2613155082
- Cited by
- 455
- References
- 48
- Citations by year
- 2026: 23 · 2025: 34 · 2024: 57 · 2023: 44 · 2022: 68 · 2021: 84 · 2020: 60 · 2019: 41 · 2018: 38 · 2017: 5 · 2015: 1
- FWCI
- 17.36
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- anti-PD-1 therapy, immune checkpoint inhibitors, pembrolizumab, nivolumab, immune-related gene expression signature, tumor-infiltrating lymphocytes, PD-L1 expression, CD8A, natural killer cells, interferon activation, progression-free survival, predictive biomarkers, non-small cell lung cancer, head and neck squamous cell carcinoma, melanoma
- MeSH terms
- Squamous Cell Carcinoma of Head and Neck, Nivolumab, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Female, Head and Neck Neoplasms, Humans, Lung Neoplasms, Male, Melanoma, Middle Aged, Gene Expression, Gene Expression Profiling, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized
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