Abstract
Identifying robust predictive biomarkers to stratify colorectal cancer (CRC) patients based on their response to immune-checkpoint therapy is an area of unmet clinical need. Our evolutionary algorithm Atlas Correlation Explorer (ACE) represents a novel approach for mining The Cancer Genome Atlas (TCGA) data for clinically relevant associations. We deployed ACE to identify candidate predictive biomarkers of response to immune-checkpoint therapy in CRC. We interrogated the colon adenocarcinoma (COAD) gene expression data across nine immune-checkpoints (PDL1, PDCD1, CTLA4, LAG3, TIM3, TIGIT, ICOS, IDO1 and BTLA). IL2RB was identified as the most common gene associated with immune-checkpoint genes in CRC. Using human/murine single-cell RNA-seq data, we demonstrated that IL2RB was expressed predominantly in a subset of T-cells associated with increased immune-checkpoint expression (P < 0.0001). Confirmatory IL2RB immunohistochemistry (IHC) analysis in a large MSI-H colon cancer tissue microarray (TMA; n = 115) revealed sensitive, specific staining of a subset of lymphocytes and a strong association with FOXP3+ lymphocytes (P < 0.0001). IL2RB mRNA positively correlated with three previously-published gene signatures of response to immune-checkpoint therapy (P < 0.0001). Our evolutionary algorithm has identified IL2RB to be extensively linked to immune-checkpoints in CRC; its expression should be investigated for clinical utility as a potential predictive biomarker for CRC patients receiving immune-checkpoint blockade.
Highlights
Colorectal cancer (CRC) is one of the world’s leading causes of cancer-related mortality
Given that Interleukin-2 receptor subunit beta (IL2RB) signaling is associated with the expansion of immune cells [17,18], we quantified the microenvironment cell populations in the The Cancer Genome Atlas (TCGA) colorectal cancer (CRC) cohort using MCP
Kaplan– Meier survival analysis demonstrated that patients in the high IL2RB subgroup had improved disease-free survival (DFS) compared to patients in the low IL2RB group. (Figure 2C, n = 322, logrank P value = 0.011)
Summary
Colorectal cancer (CRC) is one of the world’s leading causes of cancer-related mortality. Immunecheckpoints regulate the host immune response by modulating activity of immune cells in the tumor microenvironment (TME), including CD8+ cytotoxic lymphocytes (CTLs) and natural killer (NK) cells. The discovery that targeting costimulatory and inhibitory immune-checkpoints can invoke a CTL/NK cell response against tumor cells has provided the rationale for a new immunotherapy-based treatment [3,4]. An evolving armamentarium of immune-checkpoint compounds have undergone preclinical and early clinical investigation across many cancer types including CRC [2,6]. To date only CTLA-4 and PD-1 inhibitors have been FDA-approved for the treatment of dMMR metastatic CRC (mCRC) previously treated with chemotherapy [7,8]. Clinical indication for PD-1 inhibitors is currently limited to patients with dMMR and hypermutated tumors (e.g., microsatellite instability (MSI-H) and POLE mutations).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
