CTLA-4 blockade and interferon-α induce proinflammatory transcriptional changes in the tumor immune landscape that correlate with pathologic response in melanoma
Autor: | Nathan Elliott, Arjun Khunger, Ahmad A. Tarhini, Sarah Warren, Joseph M. Beechem, Erin Piazza, Andrew White, John M. Kirkwood, Alessandra Cesano, Thomas H. Smith, Xing Ren |
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Rok vydání: | 2020 |
Předmět: |
Skin Neoplasms
Transcription Genetic medicine.medical_treatment Cancer Treatment Gene Expression Metastasis White Blood Cells Cancer immunotherapy Animal Cells Basic Cancer Research Medicine and Health Sciences CTLA-4 Antigen Melanoma Immune Response Neoadjuvant therapy Multidisciplinary T Cells Combined Modality Therapy Neoadjuvant Therapy Gene Expression Regulation Neoplastic Treatment Outcome Oncology Medicine Immunotherapy Cellular Types medicine.drug Research Article Science Immune Cells Immunology Ipilimumab Disease-Free Survival Cancer Immunotherapy Proinflammatory cytokine TIGIT medicine Genetics Inflammation Blood Cells business.industry Gene Expression Profiling Interferon-alpha Biology and Life Sciences Cancers and Neoplasms Cell Biology medicine.disease Survival Analysis CTLA-4 Cancer research Clinical Immunology Neoplasm Recurrence Local Clinical Medicine business |
Zdroj: | PLoS ONE PLoS ONE, Vol 16, Iss 1, p e0245287 (2021) |
ISSN: | 1932-6203 |
Popis: | Patients with locally/regionally advanced melanoma were treated with neoadjuvant combination immunotherapy with high-dose interferon α-2b (HDI) and ipilimumab in a phase I clinical trial. Tumor specimens were obtained prior to the initiation of neoadjuvant therapy, at the time of surgery and progression if available. In this study, gene expression profiles of tumor specimens (N = 27) were investigated using the NanoString nCounter® platform to evaluate associations with clinical outcomes (pathologic response, radiologic response, relapse-free survival (RFS), and overall survival (OS)) and define biomarkers associated with tumor response. The Tumor Inflammation Signature (TIS), an 18-gene signature that enriches for response to Programmed cell death protein 1 (PD-1) checkpoint blockade, was also evaluated for association with clinical response and survival. It was observed that neoadjuvant ipilimumab-HDI therapy demonstrated an upregulation of immune-related genes, chemokines, and transcription regulator genes involved in immune cell activation, function, or cell proliferation. Importantly, increased expression of baseline pro-inflammatory genes CCL19, CD3D, CD8A, CD22, LY9, IL12RB1, C1S, C7, AMICA1, TIAM1, TIGIT, THY1 was associated with longer OS (p < 0.05). In addition, multiple genes that encode a component or a regulator of the extracellular matrix such as MMP2 and COL1A2 were identified post-treatment as being associated with longer RFS and OS. In all baseline tissues, high TIS scores were associated with longer OS (p = 0.0166). Also, downregulated expression of cell proliferation-related genes such as CUL1, CCND1 and AAMP at baseline was associated with pathological and radiological response (unadjusted p < 0.01). In conclusion, we identified numerous genes that play roles in multiple biological pathways involved in immune activation, immune suppression and cell proliferation correlating with pathological/radiological responses following neoadjuvant immunotherapy highlighting the complexity of immune responses modulated by immunotherapy. Our observations suggest that TIS may be a useful biomarker for predicting survival outcomes with combination immunotherapy. |
Databáze: | OpenAIRE |
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