Association of ATRX mutations with immunologically active characteristics in patients with MSI-prone tumors

The role of DNA damage repair deficiency in improving immune checkpoint inhibitors (ICIs) efficacy has been widely recognized. Studies have confirmed the association of gene mutations in homologous recombination (HR) with an immune-activated microenvironment. Given the crucial role of the tumor microenvironment in ICIs response, our study aimed to identify specific HR gene mutations that influence the tumor microenvironment and thus serve as potential biomarkers for ICIs in tumors that are prone to occur with microsatellite instability (MSI) events (MSI-prone tumors).

The multi-omics and clinical data of MSI-prone tumors were extracted from ICIs-treated and non-ICIs-treated cohorts. We depicted the mutation landscape of HR genes in MSI-prone tumors and identified the prognosis related HR gene mutations. We integrated multiple immunotherapy-related indicators by bioinformatics methods to characterize the anti-tumor immunity and tumor microenvironment.

ATRX, ARID1A, BRCA2 and ATM were the common top four frequently mutated HR genes in MSI-prone tumors, among which ATRX mutations were identified to have prognostic value for ICIs treatment. The bioinformatics analyses suggested that patients with ATRX mutilations (ATRX-mt) have enhanced anti-tumor immunity and inflamed tumor microenvironment in MSI-prone tumors. MSI-stratified analyses revealed the immunologically active features in both microsatellite instability-high (MSI-H) and non-MSI-H populations. There may exist a synergistic effect between ATRX mutations and MSI-H status in immune activation.

Our work found the association of ATRX mutations with immunologically active characteristics in MSI-prone tumors. The combined use of ATRX mutations and MSI-H status might have potential clinical utility for ICIs selection in MSI-prone tumors.