# Harnessing TAGAP to improve immunotherapy for lung squamous carcinoma treatment by targeting c-Rel in CD4+ T cells

## TL;DR

This study explores how targeting TAGAP in CD4+ T cells can improve immunotherapy for lung squamous carcinoma by rejuvenating T cell function and inhibiting tumor growth.

## Contribution

The study identifies TAGAP as a novel therapeutic target in LUSC by demonstrating its role in modulating CD4+ T cell activity and inhibiting c-Rel.

## Key findings

- High-risk LUSC subgroups show altered immune infiltration and increased sensitivity to Sunitinib and CTLA4 blockade.
- TAGAP overexpression enhances CD4+ T cell cytokine production and differentiation into Th1/Th17 cells while inhibiting Treg conversion.
- TAGAP's anticancer effects are partially reversed by c-Rel overexpression, highlighting its role in rejuvenating CD4+ T cells.

## Abstract

Revealing the immunosenescence, particularly in CD4+ T cell function in lung squamous carcinoma (LUSC) assists in devising individual treatment strategies. This study identifies differentially expressed genes (DEGs) between ROS1 mutated (ROS1MUT) and wild-type (ROS1WT) LUSC samples from the TCGA database. Using WGCNA, immune-related DEGs (IRGs) were screened. Prognostic signatures derived from IRGs were used to compare immune infiltration, chemotherapy sensitivity, and immune-phenotyping score (IPS) between high- and low-risk subgroups. Hub gene abundance in different cell clusters was analyzed via Sc-seq. TAGAP overexpression or silencing was employed to assess its impact on cytokines production and differentiation of CD4+ T cells, downstream c-Rel expression, and tumor progression. High-risk subgroups exhibited decreased infiltration of natural killer, follicular helper T, and CD8+ T cells, but increased plasma, CD4+ memory resting T, and macrophage M2 cells. These subgroups were more sensitive to Sunitinib and CTLA4 blockade. TAGAP expression was significantly reduced in LUSC. Overexpressing TAGAP enhanced CD4+ T cells to produce cytokines, promoted differentiation into Th1/Th17 cells, inhibited Treg conversion, and suppressed LUSC cell phenotype in vitro. TAGAP overexpression in CD4+ T cells also inhibited LUSC tumor growth and boosted immune infiltration in vivo. TAGAP’s effects on CD4+ T cells were partly reversed by c-Rel overexpression, highlighting TAGAP's role in rejuvenating CD4+ T cells and exerting anticancer effects by inhibiting c-Rel. This study elucidates the novel therapeutic potential of targeting TAGAP to modulate CD4+ T cell activity in immunotherapy for LUSC.

The online version contains supplementary material available at 10.1007/s00262-025-03960-1.