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Multi-Omics and Informatics Analysis of FFPE Tissues Derived from Melanoma Patients with Long/Short Responses to Anti-PD1 Therapy Reveals Pathways of Response.
- Source :
- Cancers; Dec2020, Vol. 12 Issue 12, p3515, 1p
- Publication Year :
- 2020
-
Abstract
- Simple Summary: Immune based therapies have benefited many melanoma patients, but many patients still do not respond. This study analyzes biospecimens obtained from patients undergoing a type of immune based therapy called anti-PD-1 to understand mechanisms of response and resistance to this treatment. The operational definition of good response utilized in this investigation permitted us to examine the biochemical pathways that are facilitating anti-PD-1 responses independent of prior therapies received by patients. Currently, there are no clinically available tests to reliably test for the outcome of patients treated with anti-PD-1 therapy. The purpose of this study was to facilitate the development of prospective biomarker-directed trials to guide therapy, as even though the side effect profile is favorable for anti-PD-1 therapy, some patients do not respond to therapy with significant toxicity. Each patient may require testing for the pathways upregulated in the tumor to predict optimal benefit to anti-PD-1 treatment. Anti-PD-1 based immune therapies are thought to be dependent on antigen processing and presentation mechanisms. To characterize the immune-dependent mechanisms that predispose stage III/IV melanoma patients to respond to anti-PD-1 therapies, we performed a multi-omics study consisting of expression proteomics and targeted immune-oncology-based mRNA sequencing. Formalin-fixed paraffin-embedded tissue samples were obtained from stage III/IV patients with melanoma prior to anti-PD-1 therapy. The patients were first stratified into poor and good responders based on whether their tumors had or had not progressed while on anti-PD-1 therapy for 1 year. We identified 263 protein/gene candidates that displayed differential expression, of which 223 were identified via proteomics and 40 via targeted-mRNA analyses. The downstream analyses of expression profiles using MetaCore software demonstrated an enrichment of immune system pathways involved in antigen processing/presentation and cytokine production/signaling. Pathway analyses showed interferon (IFN)-γ-mediated signaling via NF-κB and JAK/STAT pathways to affect immune processes in a cell-specific manner and to interact with the inducible nitric oxide synthase. We review these findings within the context of available literature on the efficacy of anti-PD-1 therapy. The comparison of good and poor responders, using efficacy of PD-1-based therapy at 1 year, elucidated the role of antigen presentation in mediating response or resistance to anti-PD-1 blockade. [ABSTRACT FROM AUTHOR]
- Subjects :
- THERAPEUTIC use of antineoplastic agents
ANTIGENS
COLLECTION & preservation of biological specimens
CANCER patients
CELLULAR signal transduction
CLASSIFICATION
COMPUTER software
GENE expression
HISTOLOGICAL techniques
IMMUNOTHERAPY
INTERFERONS
MELANOMA
MESSENGER RNA
PATIENTS
NITRIC-oxide synthases
SEQUENCE analysis
Subjects
Details
- Language :
- English
- ISSN :
- 20726694
- Volume :
- 12
- Issue :
- 12
- Database :
- Complementary Index
- Journal :
- Cancers
- Publication Type :
- Academic Journal
- Accession number :
- 148537629
- Full Text :
- https://doi.org/10.3390/cancers12123515