# The TNFR superfamily member Fn14 impacts immunity and survival in experimental gliomas and response to immune checkpoint inhibitor therapy in glioblastoma patients

## TL;DR

This study shows that Fn14, a protein in the TNFR family, affects immune responses and survival in gliomas, and its removal improves outcomes in mice and may predict poor response to immunotherapy in humans.

## Contribution

The study is the first to describe the combined role of tumor- and host-derived Fn14 in glioma immunity and survival.

## Key findings

- Fn14 knockout in tumor and host cells increased survival in glioma models.
- Fn14 loss reduced immunosuppressive macrophages and exhausted T-cells in the tumor environment.
- High Fn14 expression in human GBM correlates with poor response to immune checkpoint inhibitors.

## Abstract

Fibroblast growth factor-inducible 14 (Fn14) belongs to the TNFR superfamily. Fn14 overexpression can drive receptor-autonomous signaling, increase both cell invasion and tumor-associated macrophages/microglia (TAMMs) recruitment, and correlates with reduced survival in glioblastoma (GBM) patients and rat gliomas. While prior studies report Fn14 expression in non-tumor cells within the GBM tumor microenvironment (TME), their relative contributions to glioma pathobiology remain unclear.

Using tumor-host pairings of Fn14-positive and -knockout (-KO) cells and mice, we examined the role of Fn14 in glioma biology. Mouse glioma and human GBM datasets were analyzed at the cellular, protein, and transcriptomic levels to assess Fn14-associated changes in the glioma TME and survival outcomes.

Fn14 was found to be highly expressed in tumor cells and TAMMs in human GBM and 2 well-characterized murine glioma models. Fn14 KO in both tumor and host cells increased overall survival. Notably, this survival benefit was greater in the glioma model characterized by a more immunologically activated TME. Immunophenotyping revealed that Fn14 loss reshapes the tumor-immune landscape, reducing the presence of immunosuppressive macrophages and exhausted T-cells, suggesting that Fn14 modulates both innate and adaptive immune responses. These findings were supported by analyses of human GBM datasets, where high Fn14 expression correlated with immunosuppressive shifts and poor patient responses to immune checkpoint inhibitor therapy.

This study provides the first description of the contributions of both tumor- and host-derived Fn14 expression to tumor immunity and survival and identifies Fn14 as an important mediator of innate and adaptive immune responses in gliomas.