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
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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