Immune landscape of neoadjuvant chemoradiotherapy: involvement of MAL, a T-cell differentiation protein.

Abstract

Background: Neoadjuvant/preoperative therapy (NAT) involves the administration of chemotherapy, with or without radiation, prior to surgical resection. This approach is commonly used for locally advanced tumors to reduce tumor volume, improve resectability, and minimize the need for extensive surgical procedures. While NAT has been shown to be effective in inducing local anti-tumor immunity in potentially resectable solid tumors, the underlying molecular mechanisms remain poorly understood.

Methods: Cohort samples from pancreatic cancer patients who underwent NAT (n = 26) and those who did not (n = 20) were analyzed. Changes in the immune microenvironment induced by NAT were assessed using stratified bioinformatic approaches, including heatmap analysis of immune-related genes selected via Gene Ontology, Gene Set Enrichment Analysis (GSEA) with the immunologic signature database, and Ingenuity Pathway Analysis (IPA). Findings were further validated through immunohistochemical analysis.

Results: A comprehensive, stratified evaluation integrating pathological and bioinformatic approaches revealed that NAT induced the upregulation of 212 genes, including DC-SIGN (CD209), and activated 13 immune-associated pathways, such as T-cell receptor (TCR) signaling. Additionally, NAT promoted an increased shift toward CD8 (+) T-cell populations through the upregulation of MAL (T-cell differentiation protein). Immunohistochemical analysis further confirmed a significant accumulation of DC-SIGN (+) dendritic cells and MAL (+) lymphocytes in NAT-treated patients.

Conclusions: NAT enhances anti-tumor immunity by promoting CD8 (+) T-cell generation through the activation of DC-SIGN (+) dendritic cells and MAL (+) lymphocytes. This study is the first to report an increase in MAL (+) lymphocytes following NAT. Given its potential significance, further investigation in other solid tumors treated with NAT is warranted.