As a key regulator of hippo signaling pathway, LATS1 (large tumor suppressor 1) gene encodes a Ser/Thr protein kinase which plays a crucial role in cellular transformation and tumorigenesis. But it remains to be determined if LATS1 mutation may have true biologic relevance and can independently predict responses to immune checkpoint inhibitors (ICIs). Our research aims to elucidate its mutation association with ICI efficacy.
In order to investigate the correlation between LATS1 mutation and ICI efficacy in the bladder cancer, we used cBioportal to collect clinical and mutation data of 215 ICI-treated bladder cancers from MSKCC cohort. Gene expression and WES data of 413 samples were obtained from the TCGA database for further analysis of the differences of potential biological mechanisms between LATS1-mutant and LATS1-wildtype tumors. Tumor mutation burden (TMB) was calculated as the total number of somatic non-synonymous mutations per megabase in both MSKCC and TCGA cohorts. CIBERSORT algorithm was applied to infer 22 human immune cell type proportions in TCGA advanced bladder cancers.
In the MSKCC cohort, we observed 5.12% (11/215) patients harbored LATS1 mutation. As indicated by Kaplan-Meier analysis, the patients with LATS1 mutation had significantly better OS in the MSKCC cohort (P = 0.023, HR = 0.23, 95%CI: 0.06-0.93). This link was still existing when controlling for age, sex, stage, TMB and therapy type in the multivariate Cox regression analysis (P = 0.039, HR = 0.22, 95%CI = 0.05-0.93). As expected, the LATS1-mutant group had higher TMB than that of the LATS1-wildtype group in both the MSKCC cohort (median: 27.55 vs. 7.87, P <0.001) and TCGA cohort (median: 7.74 vs. 4.62, P = 0.042). Immune cell analysis showed that NK activated cells were abundant in the LATS1-mutant group (P = 0.05). This result indicated LATS1-mutant tumors had an activated antitumor immune microenvironment.
LATS1 mutations might be a potential biomarker to predict the efficacy of immunotherapy for bladder cancer. Considering the heterogeneity among the patients and other confounding factors, further prospective validation cohorts are warranted.
Clinical trial identification
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All authors have declared no conflicts of interest.