What does this research mean for the field?

The Tumor Resistance Instability Score (TRIS), a composite transcriptomic biomarker, predicts non-response to pembrolizumab in melanoma but fails to replicate in nivolumab-treated patients, potentially due to drug-class differences or insufficient statistical power. Novelty: ClaimNovelty.METHODOLOGICAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to establish TRIS as a predictive biomarker for anti-PD1 immunotherapy response in melanoma.

May 16, 2026Open Access

TRIS (Tumor Resistance Instability Score): A Transcriptomic Biomarker for Anti-PD1 Immunotherapy Response Prediction in Melanoma -- Discovery and Negative Replication

Key Points

This research aims to establish TRIS as a predictive biomarker for anti-PD1 immunotherapy response in melanoma.
Integration of six tumor resistance pathways using ssGSEA to develop TRIS.
Discovery cohort GSE78220 (n=26) assessed pembrolizumab response; replication cohort GSE91061 (n=33) assessed nivolumab.
Statistical analyses included Mann-Whitney tests, AUROC, and permutation tests.
In GSE78220, TRIS was significantly higher in non-responders (Mann-Whitney p=0.023, Cohen d=0.929, AUROC=0.734).
Strongest individual pathways were hypoxia/HIF (p=0.009) and immune evasion (p=0.005).
Replication in GSE91061 yielded a negative result (p=0.585, AUROC=0.478), attributed to differences in drug classes.

Abstract

We propose TRIS (Tumor Resistance Instability Score), a composite ssGSEA biomarker integrating six tumor resistance pathways (EMT/invasion, stemness, hypoxia/HIF, DNA damage repair, immune evasion, and survival/anti-apoptosis) to predict anti-PD1 immunotherapy non-response in melanoma. Discovery cohort GSE78220 (pembrolizumab, n=26): TRIS significantly higher in non-responders (Mann-Whitney p=0.023, Cohen d=0.929, AUROC=0.734, permutation p=0.0004). Hypoxia/HIF (p=0.009) and immune evasion (p=0.005) pathways show strongest individual signals. Attempted replication in GSE91061 (nivolumab, n=33): negative result (p=0.585, AUROC=0.478), attributed to drug-class differences (pembrolizumab vs nivolumab) and insufficient statistical power (Responder n=10). Both positive and negative results are reported in full accordance with scientific integrity. TRIS is part of the Geometric Systems Medicine framework integrating transcriptome-level (TRIS) and protein geometry-level (FIS) analyses of drug resistance.

TRIS (Tumor Resistance Instability Score): A Transcriptomic Biomarker for Anti-PD1 Immunotherapy Response Prediction in Melanoma -- Discovery and Negative Replication

Key Points

Abstract

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