Immune microenvironment in elderly patients with rectal cancer

Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with its incidence rates increasing with age. Age is a significant prognostic factor in CRC, and different age groups exhibit distinct characteristics. The aim of this study is to analyse the immunosurveillance mechanisms in elderly patients with rectal cancer to identify differences compared to patients who develop rectal cancer at a younger age. Methods: We conducted a retrospective study using the IMMUNOREACT database, focusing on the gene expression related to immune surveillance in the healthy rectal mucosa surrounding the tumour. From the IMMUNOREACT database, we specifically excluded individuals diagnosed with T4 and/or M1 stages of cancer; a total of 952 patients were successfully enrolled in the study. A sub-analysis of this cohort was undertaken to explore age-related differences in the immune microenvironment within the healthy mucosa; the analysis compared patients younger than 75 years old (683 patients) with those older than 75 (269 patients). Furthermore, we conducted an additional sub-analysis to examine differences between patients who had undergone neoadjuvant therapy (427 patients) and those who were therapy-naïve (509 patients). Results: Our findings revealed that elderly patients exhibited significantly higher expression levels of epithelial CD80 and T helper cells compared to their younger counterparts. This observation led us to hypothesize that older individuals might develop cancer later in life due to more effective immunosurveillance mechanisms. However, our study also uncovered that these elderly patients had a lower CD8/CD4 ratio, along with more frequent expression of PD-L1 and a tendency towards higher expression of CTLA-4. Prolonged signalling through these pathways contributed to "lymphocyte exhaustion," a state in which T cells lost their ability to proliferate and effectively eliminate tumour cells, thereby weakening the anti-tumour immune response. Conclusions: Despite these seemingly robust immunosurveillance markers, elderly individuals still develop cancer, suggesting that the aging immune system, while initially more vigilant, may eventually succumb to the effects of lymphocyte exhaustion. Furthermore, when we stratified our study population into therapy-naïve and chemo-radiotherapy-treated patients, it became evident that the observed differences in immunosurveillance between younger and older patients were no longer present in the group that received neoadjuvant treatments. This finding suggests that neoadjuvant chemo-radiotherapy may have a profound impact on the rectal mucosa, potentially altering the immunosurveillance patterns that differentiate age groups.