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Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy.

ABSTRACT: Immune-related adverse events (irAEs) can impair the effectiveness and safety of immune checkpoint inhibitors (ICIs) and restrict the clinical applications of ICIs in oncology. The predictive biomarkers of irAE are urgently required for early diagnosis and subsequent management. The exact mechanism underlying irAEs remains to be fully elucidated, and the availability of predictive biomarkers is limited. Herein, we performed data mining by combining pharmacovigilance data and pan-cancer transcriptomic information to illustrate the relationships between alternative splicing characteristics and irAE risk of ICIs. Four distinct classes of splicing characteristics considered were associated with splicing factors, neoantigens, splicing isoforms, and splicing levels. Correlation analysis confirmed that expression levels of splicing factors were predictive of irAE risk. Adding DHX16 expression to the bivariate PD-L1 protein expression-fPD1 model markedly enhanced the prediction for irAE. Furthermore, we identified 668 and 1,131 potential predictors based on the correlation of the incidence of irAEs with splicing frequency and isoform expression, respectively. The functional analysis revealed that alternative splicing might contribute to irAE pathogenesis via coordinating innate and adaptive immunity. Remarkably, autoimmune-related genes and autoantigens were preferentially over-represented in these predictors for irAE, suggesting a close link between autoimmunity and irAE occurrence. In addition, we established a trivariate model composed of CDC42EP3-206, TMEM138-211, and IRX3-202, that could better predict the risk of irAE across various cancer types, indicating a potential application as promising biomarkers for irAE. Our study not only highlights the clinical relevance of alternative splicing for irAE development during checkpoint immunotherapy but also sheds new light on the mechanisms underlying irAEs.

SUBMITTER: He X

PROVIDER: S-EPMC8652050 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Although immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with many advanced malignancies, only 15-60% of patients respond, leaving a broad swath of patients who do not derive benefit. Identifying biomarkers to optimally identify patients who will benefit from ICIs is a major research focus for the oncology community. Thus far, predictive biomarker research has focused on tumor signatures such as microsatellite instability, programmed death-ligand 1 (PD-L1) expression and tumor mutational burden; clinical biomarkers have been far less studied. One potential clinical biomarker for ICI response in patients is immune-related adverse event (IRAE) onset.IRAEs are thought to represent bystander effects from activated T-cells and it is plausible that patients responding to ICIs would have greater likelihood of autoimmune toxicities (e.g. due to a more competent/treatment-responsive immune system, or cross-reactivity between tumor and host tissue). Earlier studies in melanoma patients however, suggested no association between IRAE onset and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody efficacy. In contrast, a growing body of literature suggests IRAE onset is predictive of anti-programmed cell death protein 1 (PD-1) and anti-PD-L1 antibody response across a variety of solid tumors. Most of these studies report that patients who experienced IRAEs demonstrate marked improvements in progression-free survival, overall survival and overall response rate compared to those lacking toxicity.Key questions regarding the association between IRAE onset and ICI efficacy remain. The most pertinent of these involve whether the association is only relevant for patients treated with anti-PD-1 and anti-PD-L1 antibodies and whether IRAE site, severity, timing of onset and management influence ICI efficacy. Herein, we discuss the seminal studies which have begun to address these questions and have shaped the narrative about the predictive value of IRAE onset for patients on ICIs, in this review.

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Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy.

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