Evaluating the immune landscape in early onset colorectal cancer patients.

Abstract

e15711 Background: The incidence of early-onset colorectal cancer (EOCRC) is rising, but little is known about the immune microenvironment. Our prior work has shown altered transcriptomic signatures in EOCRC patients compared to their average-age counterparts, particularly the downregulation of certain immune checkpoint inhibitor pathways in EOCRC. In this analysis, we seek to elucidate the expression of common immunotherapy targets in EOCRC patients (younger than 50 years old at diagnosis) compared to average onset colorectal cancer (AOCRC) patients (defined as 50 years or older at diagnosis). We also seek to compare the immune cell composition between EOCRC and AOCRC tumor microenvironments. Methods: We queried The Cancer Genome Atlas ( TCGA ) CRC dataset. Patients were separated into younger and older populations. Participant transcriptional profiles were compared and assessed via differential gene expression analysis (DESeq2), with particular attention to common immunotherapy targets (TNFRSF9/4-1BB, LAG3, CD40, CD 276/B7-H3, PD-L1, PD-L2, CD70, TIM-3, CD27, CTLA4, ICOS, TIGIT, BTLA, OX40, GITR, and CD47). The proportions of different cell populations were estimated using the cell fraction analysis module from CIBERSORT. The Wilcoxon signed-rank test was used for the group comparison with significance set at p≤0.05. Results: Across the TCGA database, we assessed a total of 397 patient samples (n = 349 AO n = 48 EO). Amongst the patients in the database, BTLA expression was increased in EOCRC patients (p = 0.01). CD47 expression was noted to be less in the EOCRC cohort (p = 0.03). While looking at the immune cell composition, M1 macrophages were found to be less abundant in the EOCRC cohort, however this was not statistically significant. Other differences in immune cell composition were also noted in this analysis, however they lacked statistical significance. Conclusions: Our analysis shows differential expression of common immunotherapy targets between EOCRC and AOCRC patients in the TCGA database. Available data suggests decreased CD 47 expression may lead to decreased immune cell infiltration which may cause a decreased anti-tumor immune response in EOCRC patients. In addition, available data suggests BTLA expression can inhibit the function of CD8 cancer specific T cells further contributing to decreased immune function and suggesting potential decreased immunotherapy response. The present analysis complements our previous work, suggesting that EOCRC patients may have an altered immune environment which may lead to decreased response to immunotherapy compared to AOCRC patients. Further studies are needed to confirm our hypothesis.