TCCIA: A Comprehensive Resource for Exploring CircRNA in Cancer Immunotherapy

Abstract Background Immunotherapies targeting immune checkpoints have gained increasing attention in cancer treatment, emphasizing the need for predictive biomarkers. Circular RNAs (circRNAs) have emerged as critical regulators of tumor immunity, particularly in the PD-1/PD-L1 pathway, and have shown potential in predicting immunotherapy efficacy. Yet, the detailed roles of circRNAs in cancer immunotherapy are not fully understood. While existing databases focus on either circRNA profiles or immunotherapy cohorts, there is currently no platform that enables the exploration of the intricate interplay between circRNAs and anti-tumor immunotherapy. A comprehensive resource combining circRNA profiles, immunotherapy responses, and clinical outcomes is essential to advance our understanding of circRNA-mediated tumor-immune interactions and to develop effective biomarkers. Methods To address these gaps, we constructed the Cancer CircRNA Immunome Atlas (TCCIA), the first database that combines circRNA profiles, immunotherapy response data, and clinical outcomes across multi-cancer types. The construction of TCCIA involved applying standardized preprocessing to the raw sequencing FASTQ files, characterizing circRNA profiles using an ensemble approach based on four established circRNA detection tools, analyzing tumor immunophenotypes, and compiling immunotherapy response data from diverse cohorts treated with immune-checkpoint blockades (ICBs). Results TCCIA encompasses over 4,000 clinical samples obtained from 25 cohorts treated with ICBs along with other treatment modalities. The database provides researchers and clinicians with a cloud-based platform that enables interactive exploration of circRNA data in the context of ICB. The platform offers a range of analytical tools, including browse of identified circRNAs, visualization of circRNA abundance and correlation, association analysis between circRNAs and clinical variables, assessment of the tumor immune microenvironment, exploration of tumor molecular signatures, evaluation of treatment response or prognosis, and identification of altered circRNAs in immunotherapy-sensitive and resistant tumors. To illustrate the utility of TCCIA, we showcase two examples, including circTMTC3 and circMGA, by employing analysis of large-scale melanoma and bladder cancer cohorts, which unveil distinct impacts and clinical implications of different circRNA expression in cancer immunotherapy. Conclusions TCCIA represents a significant advancement over existing resources, providing a comprehensive platform to investigate the role of circRNAs in immuno-oncology. What is already known on this topic Prior knowledge indicated that circRNAs are involved in tumor immunity and have potential as predictive biomarkers for immunotherapy efficacy. However, there lacked a comprehensive database that integrated circRNA profiles and immunotherapy response data, necessitating this study. What this study adds This study introduces TCCIA, a database that combines circRNA profiles, immunotherapy response data, and clinical outcomes. It provides a diverse collection of clinical samples and an interactive platform, enabling in-depth exploration of circRNAs in the context of checkpoint-blockade immunotherapy. How this study might affect research, practice or policy The findings of this study offer valuable insights into the roles of circRNAs in tumor-immune interactions and provide a resource for researchers and clinicians in the field of immune-oncology. TCCIA has the potential to guide personalized immunotherapeutic strategies and contribute to future research, clinical practice, and policy decisions in checkpoint-blockade immunotherapy and biomarker development.