A 7-Gene Expression Signature Predicts Immune Microenvironment Remodeling and Neoadjuvant Chemo-Immunotherapy Response in Lung Squamous Cell Carcinoma

Shaoling Li¹Junhong Guo¹Yan Huang¹Zhengwei Dong¹Ranyue Wang¹Huifang Liu¹Yaoqi Xiao²Jin Wang³Xing Li³Zhan Huang³Tao Hu³Changbin Zhu³Likun Hou¹Chunyan Wu^1*

• ¹Department of Pathology, Tongji University Affiliated Shanghai Pulmonary Hospital, Shanghai, China
• ²Nanchang University, Nanchang, China
• ³Amoy Diagnostics Co Ltd, Xiamen, China

Background Neoadjuvant chemo-immunotherapy (NCI) has significantly improved outcomes in advanced lung squamous cell carcinoma (LUSC). However, some patients remain resistant to NCI, resulting in poor outcomes. The mechanisms behind this resistance remain unclear. Methods Forty LUSC patients receiving NCI were selected and categorized into major pathological response (MPR) and non-MPR groups based on their pathological response. Pre- and post-treatment samples underwent bulk RNA sequencing (RNA-seq) to assess the composition of immune cell subtypes, including T cells, B cells, NK cells, dendritic cells, and macrophages. A panel of 134 immune cell subtypes were further analyzed to differentiate between “cold” and “hot” tumor immune phenotypes. Results After surgery, 75% of patients achieved MPR, while 25% were classified as non-MPR. In MPR patients, NCI transformed the tumor immune microenvironment (TME) from a "cold" to a "hot" phenotype, characterized by increased anti-tumor immune activity. We identified seven genes potentially linked to NCI response. Among these, HOXC13 was associated with reduced immune-cell infiltration and inferior NCI response.. High HOXC13 expression was associated with worse progression-free survival (PFS) and overall survival (OS), as confirmed by the OAK database. Conclusions NCI altered the TME and was linked to treatment response in LUSC. Identifying predictors of immunotherapy efficacy, such as HOXC13, provides potential strategies to overcome resistance in clinical practice.