A 12-chemokine Gene Signature Is Associated With an Enhanced Cancer-immunity Cycle and Is Relevant for Precision Immunotherapy

Abstract Background: Advances in the understanding of checkpoint blockade immunotherapy have suggested that boosting the cancer-immunity cycle (CIC) can help induce regression of tumors. However, good efficacy only occurs in a subset of patients. Predictive biomarkers that can reflect the tumor microenvironment (TME) and CIC may have great potential. More recently, the presence of intratumoral tertiary lymphoid structures (TLSs) has also been correlated with clinical benefit in patients.Methods: In this study, we comprehensively measured the immunogram scores (IGSs) for the CIC and explored the associations between immunological and mutational features and a 12-chemokine metagene TLS signature in data from The Cancer Genome Atlas (TCGA). Three immunotherapy datasets were further applied for validation.Results: In the TCGA dataset, we observed that the 12-chemokine TLS signature score was positively associated with a boosted CIC, as represented by increased tumor mutational burden (TMB) and neoantigen burden (TNB), enriched immune cell infiltration, and elevated cytolytic activity and checkpoint expression. Specifically, in bladder cancer and melanoma, a high 12-chemokine TLS signature score was found to potentially reflect an expanded CIC phenotype characterized by high TNB and an immune-inflamed feature. The predictive and prognostic value of the 12-chemokine TLS signature was further validated in several immunotherapy datasets.Conclusion: The score of a 12-chemokine metagene signature may serve as a pancancer marker of the immune-active phenotype. The 12-chemokine TLS signature showed promise as a predictive and prognostic biomarker for ICB efficacy, especially in melanoma and bladder cancer.