Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer

Abstract

BackgroundNeoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC.MethodsWe analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LARC cohorts, including a LARC patient RNA sequencing (RNA-seq) dataset from our cohort and GSE15781 and GSE94104 datasets.ResultsGene ontology analysis showed that preoperative CRT significantly enriched the immune response in LARC tissues. Moreover, gene set enrichment analysis revealed six significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways associated with downregulated genes, including mismatch repair (MMR) genes, in LARC tissues after CRT in all three cohorts. Radiation also induced apoptosis and downregulated various MMR system-related genes in three colorectal cancer cells. One patient with LARC showed a change in microsatellite instability (MSI) status after CRT, as demonstrated by the loss of MMR protein and PCR for MSI. Moreover, CRT significantly increased tumor mutational burden in LARC tissues. CIBERSORT analysis revealed that the proportions of M2 macrophages and CD8 T cells were significantly increased after CRT in both the RNA-seq dataset and GSE94104. Notably, preoperative CRT increased various immune biomarker scores, such as the interferon-γ signature, the cytolytic activity and the immune signature.ConclusionsTaken together, our findings demonstrated that neoadjuvant CRT modulated the immune-related characteristics of LARC, suggesting that neoadjuvant CRT may enhance the responsiveness of LARC to immunotherapy.

Biomarkers for Predicting the Response to Radiation-Based Neoadjuvant Therapy in Rectal Cancer

“…This has also been considered to represent an in situ vaccination [34]. Substantial evidence indicates the tumour microenvironment is a vital factor and a reliable marker for predicting the response to certain treatments, the progression of tumours, and the clinical outcome of patients [94]. Thanks to rapid advances in next-generation sequencing technology over the past decade, the relationship between tumour microenvironment, immune regulation-associated biomarkers, and the response to chemoradiotherapy have all been areas of active investigation.…”

“…Meanwhile, nCRT was shown to boost various biomarker scores of immune-associated characteristics in cancer patients, including the immune signature, cytolytic activity and interferon-γ signature. nCRT therefore has the potential to strengthen the therapeutic response of RC patients to immunotherapy [94].…”

PD-1 Inhibitor Combined With Radiotherapy and GM-CSF (PRaG) in Patients With Metastatic Solid Tumors: An Open-Label Phase II Study

“…Radiotherapy can upregulate PD-L1 expression (4,15), and emerging evidence has shown clinical efficacy of radiotherapy in combination with pembrolizumab in metastatic NSCLC (16)(17)(18), especially in those PD-L1 negative subgroups (17). Furthermore, chemo-radiotherapy (CRT) can increase TMB and dysregulation of MMR system-related genes, thus altering MSI status (19). For instance, in a phase II trial, MSS colorectal and pancreatic adenocarcinoma patients, considered insensitive to anti-PD-1 immunotherapy, could benefit from the combined radiotherapy and immunotherapy (20).…”

An immuno-score signature of tumor immune microenvironment predicts clinical outcomes in locally advanced rectal cancer

“…Recently, a growing number of immune analyses based on gene expression profiles are used to predict the prognosis of LARCs (7)(8)(9)(10). However, comprehensive analysis of bulk data remains challenging due to technical design differences, platform variations, and batch effects (11).…”