WCLC 2025 - Posters & ePosters-EP.06.38 HLA-DQB1 Predicts Immunotherapy Response in NSCLC Through Augmented TCR Signaling

Pdf Summary

This study identifies HLA-DQB1 as a prognostic biomarker predicting immunotherapy response in non-small cell lung cancer (NSCLC) via enhanced T-cell receptor (TCR) signaling mediated by ZAP70 activation. Transcriptomic sequencing of tumors and normal lung tissues from NSCLC patients with complete pathological response (CPR) and non-CPR following immunotherapy revealed significant molecular differences. The CPR group showed upregulation of immune-related genes, including TCR components (CD3D, CD8A) and tumor suppressors (FUCA1), alongside suppression of epithelial-mesenchymal transition markers, indicating an active anti-tumor immune microenvironment.<br /><br />Pathway analysis demonstrated that immune-related processes, particularly T helper cell differentiation and TCR signaling pathways, were predominantly activated in the CPR group. In contrast, non-CPR tissues exhibited activation of inflammatory and angiogenic pathways such as interleukin-6 and VEGF signaling. Comparative analysis with normal tissues confirmed tumor-specific activation of inflammatory and cancer pathways.<br /><br />A key finding was the progressive downregulation of HLA-DQB1 from CPR to non-CPR and tumor tissues, linked to diminished activation of ZAP70, a kinase critical for initiating TCR signaling cascades via second messenger generation. HLA genotyping ruled out allelic variation as a factor, highlighting expression levels of HLA-DQB1 as the prognostic element. The study suggests that HLA-DQB1 sustains anti-tumor immunity by promoting ZAP70-mediated TCR activation, and its loss may contribute to immune evasion and therapy resistance.<br /><br />In conclusion, HLA-DQB1 serves as a predictive biomarker of immunotherapy efficacy in NSCLC and represents a potential therapeutic target to augment TCR signaling and overcome immune escape mechanisms. These insights support incorporating HLA-DQB1 status in patient stratification and developing combination strategies to improve immunotherapy outcomes.

Asset Subtitle

Yaxian Yang

Meta Tag

Speaker Yaxian Yang

Topic Pathology and Biomarkers

Keywords

HLA-DQB1

prognostic biomarker

immunotherapy response

non-small cell lung cancer

T-cell receptor signaling

ZAP70 activation

transcriptomic sequencing

immune microenvironment

epithelial-mesenchymal transition

immune evasion