CTLA-4 blockade and interferon-α induce proinflammatory transcriptional changes in the tumor immune landscape that correlate with pathologic response in melanoma

• DOI: 10.1371/journal.pone.0245287
• Publication Date: 2021-01-12T21:28:27Z
• Authors: Arjun Khunger; Erin Piazza; Sarah Warren; Thomas H. Smith; Xing Ren; Andrew White; Nathan Elliott; Alessandra Cesano; Joseph M. Beechem; John M. Kirkwood; Ahmad A. Tarhini
• Keywords: TIGIT; Immune checkpoint; Proinflammatory cytokine

Patients with locally/regionally advanced melanoma were treated neoadjuvant combination immunotherapy high-dose interferon α-2b (HDI) and ipilimumab in a phase I clinical trial. Tumor specimens obtained prior to the initiation of therapy, at time surgery progression if available. In this study, gene expression profiles tumor (N = 27) investigated using NanoString nCounter® platform evaluate associations outcomes (pathologic response, radiologic relapse-free survival (RFS), overall (OS)) define biomarkers associated response. The Inflammation Signature (TIS), an 18-gene signature that enriches for response Programmed cell death protein 1 (PD-1) checkpoint blockade, was also evaluated association survival. It observed ipilimumab-HDI therapy demonstrated upregulation immune-related genes, chemokines, transcription regulator genes involved immune activation, function, or proliferation. Importantly, increased baseline pro-inflammatory CCL19 , CD3D CD8A CD22 LY9 IL12RB1 C1S C7 AMICA1 TIAM1 TIGIT THY1 longer OS ( p < 0.05). addition, multiple encode component extracellular matrix such as MMP2 COL1A2 identified post-treatment being RFS OS. all tissues, high TIS scores 0.0166). Also, downregulated proliferation-related CUL1 CCND1 AAMP pathological radiological (unadjusted 0.01). conclusion, we numerous play roles biological pathways suppression proliferation correlating pathological/radiological responses following highlighting complexity modulated by immunotherapy. Our observations suggest may be useful biomarker predicting