A myeloid IFN gamma response gene signature correlates with cancer prognosis

Abstract

Background: The IFN-γ cytokine plays a dual role in anti-tumor immunity, enhancing immune defense against cancer cells while promoting tumor survival and progression. Its influence on prognosis and therapeutic responses across cancer types remains unclear.

Objective: This study aimed to perform a pan-cancer analysis of IFN-γ response genes to determine their prognostic significance and evaluate their impact on clinical outcomes and anti-PD1 immunotherapy responses.

Methods: Using multiple datasets, 46 IFN-γ response genes were identified as prognostic for disease-specific survival, and their expression was used to construct the IFN-γ Response Gene Network Signature (IFGRNS) score. The prognostic and therapeutic relevance of the IFGRNS score was assessed across cancer types, considering tumor pathology, genomic alterations, tumor mutation burden, and microenvironment. Single-cell transcriptomic analysis identified cellular contributors, and a murine pancreatic cancer (PAN02) model was used to validate findings with anti-PD1 therapy.

Results: The IFGRNS score emerged as a robust prognostic indicator of survival, with higher scores correlating with worse outcomes in most cancer types. The prognostic significance of the score was influenced by factors such as cancer type, tumor pathology, and the tumor microenvironment. Single-cell analysis revealed that myeloid cells, particularly the M2 macrophage subtype, demonstrated high levels of IFGRNS expression, which was associated with tumor progression. A negative correlation was observed between the IFGRNS score and outcomes to anti-PD1 immunotherapy in urologic cancers, where patients with higher scores showed worse prognosis and lower response rates to therapy. Experimental validation in the PAN02 murine model confirmed that anti-PD1 therapy significantly reduced tumor size and IFGRNS expression in M2 macrophages, supporting the clinical findings.

Conclusions: The IFGRNS score is a novel prognostic indicator for survival and therapeutic responses in cancer. These findings underline the complexity of IFN-γ signaling and suggest potential applications for the IFGRNS score in cancer diagnosis, prognosis, and immunotherapy.Novelty & impact statements: IFN-γ response genes play a significant role in tumour biology, yet comprehensive analysis across various cancers is limited. This study identifies a novel prognostic biomarker, the IFGRNS score, which is elevated in myeloid lineage cells and correlates with survival across multiple cancers. The IFGRNS score is also associated with tumour pathology, immune microenvironment, and immunotherapy response, highlighting its diagnostic and therapeutic potential in cancer management.

Keywords

anti-PD1 immunotherapy / IFN-γ response genes / LASSO / pan-cancer / prognosis / tumour microenvironment

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.