Abstract
Immune checkpoint inhibitors (ICIs) have shown promising results in bladder cancer (BC). However, only some patients respond to ICIs. DNA repair defects (DDR) play an important role in the therapeutic response of bladder cancer. Therefore, we aimed to elucidate the association between ICIs in bladder cancer and ataxia telangiectasia mutated (ATM), a core component of the DNA repair system. From a collected immunotherapy cohort (n = 210) and The Cancer Genome Atlas (TCGA)-Bladder cancer cohort, which were both retrieved from publicly available resources, we performed a series of analyses to evaluate the prognostic value and potential mechanism of ATM in bladder cancer immunotherapy. We found that ATM-mutant (ATM-MT) bladder cancer patients derived greater benefit from ICIs [overall survival (OS), hazard ratio (HR) = 0.28, [95% confidence interval (CI), 0.16 to 0.51], P = 0.007] and showed a higher mutation load (P < 0.05) and immunogenicity (P < 0.05) than ATM-wild-type (ATM-WT) patients. The immune inflammatory response to antigenic stimulation, the regulation of the IFN pathway and the macrophage activation pathway were significantly enriched in the ATM-MT group (NES > 1, P < 0.05), while insulin-like growth factor receptor signaling pathways and vasculogenesis were significantly downregulated (NES < −1, P < 0.05). ATM mutation significantly upregulated the number of DNA damage repair pathway gene mutations (P < 0.05). ATM mutations resulted in increased bladder cancer sensitivity to 29 drugs (P < 0.05), including cisplatin and BMS-536924, an IGF-1R inhibitor. Our results demonstrate the importance of ATM as a prognostic signature in bladder cancer and reveal that ATM may impact the effects of ICIs by acting on the tumor immune microenvironment.
Highlights
As one of the most common cancers in the world, bladder cancer (BC) is more common in men than in women (Antoni et al, 2017)
We found that the overall survival (OS) time of the ataxia telangiectasia mutated (ATM)-MT bladder cancer patients treated with immune checkpoint inhibitors (ICIs) was longer than that of the ATM-WT patients [Figure 1A, hazard ratio (HR) = 0.28, [95% confidence interval (CI), 0.16 to 0.51], P = 0.007]
We found that ATM gene mutation did not predict prognosis in the The Cancer Genome Atlas (TCGA) cohort patients who did not receive ICI treatment (Figure 1B: OS, n = 410, HR = 0.76 [95% CI, 0.49 to 1.16], P = 0.251; Figure 1C: progression-free survival (PFS), n = 411, HR = 0.65 [95% CI, 0.43 to 1.00], P = 0.09; Figure 1D: diseasefree survival (DFS), n = 188, HR = 0.64 [95% CI, 0.26 to 1.57], P = 0.401)
Summary
As one of the most common cancers in the world, bladder cancer (BC) is more common in men than in women (Antoni et al, 2017). The high mutational load of bladder cancer confers high immunogenicity, which makes bladder cancer a good candidate for immunotherapy strategies, such as immune checkpoint blockade (ICB) (Chabanon et al, 2016). In 2016, immune checkpoint inhibitors (ICIs) were approved for the treatment of bladder cancer patients with advanced refractory disease or who were ineligible platinum chemotherapy, improving patient prognosis (Zibelman et al, 2016). ICB therapy against the checkpoint axis of programmed death ligand-1 (pd-l1)/pd-1 has shown some promising results as a UC therapy (Sharma et al, 2017), only 20–30% of UC patients have a partial or complete response to ICI therapy (Mariathasan et al, 2018). The identification of new potential biomarkers to guide targeted clinical therapy and increase the proportion of patients with bladder cancer responsive to immunotherapy is urgently needed
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