The prevalence of mutant ARID1 and its role in the prognosis of NSCLC
According to the datasets acquired from the cBioPortal for Cancer Genomics, ARID1 mutation is common among NSCLC patients. As shown in Figure 1A, the mutation frequencies of the subunits of ARID1 including ARID1A and ARID1B were 7% and 4% in NSCLC patients, respectively. As far as we are concerned, gene mutations or hypermethylation lead to low ARID1 protein expression [24-25], therefore, we further investigated the relationship between the survival of NSCLC patients and the expression of the ARID1 protein. Figure 1B and Figure 1C describe the relationships between the disease-free survival (DFS) or OS of NSCLC patients and the expression of ARID1A or ARID1B. As shown in the figure, ARID1A and ARID1B both are convincing biomarkers for NSCLC prognosis with compelling efficiency, and ARID1A or ARID1B deficiency was significantly related to the poor prognosis of NSCLC (ARID1A [DFS: P<0.0001; OS: P<0.0001]; ARID1B [DFS: P=0.0045; OS: P<0.0001]).
ARID1A or ARID1B mutation correlates with an improved outcome for ICIs treatment
The relationship between ARID1A or ARID1B mutation and the outcome of ICIs treatment was then studied. Through systematic analyses of the datasets from the cBioPortal for Cancer Genomics, we found that both ARID1A and ARID1B mutations were associated with an improved outcome for ICIs treatment in advanced NSCLC patients. As shown in Figure 2A, more responders (CR+PR+SD) were confirmed in the mutant-type (MT) group than in the wild-type (WT) group for patients harboring ARID1A (50% versus 19%, P=0.045) or ARID1B (50% versus 16%, P=0.034) mutations. Figure 2B displays the median PFS (mPFS) with ICIs treatment for the two groups. Patients harboring ARID1A (6.8 months versus 5.5 months, P=0.313) or ARID1B (10.0 months versus 5.4 months, P=0.032) mutations benefited more from treatment and achieved a longer PFS time than those in the WT group. Survival analyses for ICIs treatment were then performed as shown in Figure 2C. Compared with those in the WT group, patients harboring mutant ARID1B achieved significant survival benefits with treatment (P=0.031). However, although a trend toward a difference existed for the survival curve of patients harboring mutant ARID1A, no statistical significance was found (P=0.145).
Establishment of a prognostic nomogram for the prognosis of ICIs treatment in NSCLC
Eighty-six patients of the selected NSCLC cohort with integrated information on clinical features, targeted sequencing and PD-L1 expression evaluated by immunohistochemistry (IHC) were involved in the construction of the novel nomogram. First, univariate analyses were performed to identify variables to include in nomogram construction. As shown in Figure 3A to Figure 3F, multiple variables were confirmed to be significantly associated with the prognosis of ICI treatment, including EGFR mutation (P=0.021), ARID1B mutation (P=0.024), PD-L1 expression (P=0.010), TMB (P=0.012), treatment lines (P=0.003) and smoking history (P=0.007). Through the univariate analyses, we found that patients with mutant ARID1B, elevated PD-L1 expression (≥50% percentage positive staining), a high TMB value (≥75th percentage) or a history of smoking could benefit from ICIs treatment, while patients harboring mutant EGFR might not derive survival benefits from ICIs treatment. In addition, first-line administration of ICIs in advanced NSCLC patients might be a better choice than later administration. The nomogram based on these variables was then established as shown in Figure 3G. In total, 3 types of patient information, including the clinical information, pathological information and genomic signatures, were included in the nomogram. Through this novel nomogram, physicians could easily obtain a score based on the Cox regression model for each variable listed in the graph, and then the total number would be assessed as the sum of all variable scores. Therefore, the survival risks of ICIs treatment for advanced NSCLC patients could be quantified before treatment. The C-index for this prognostic model was 0.71, which suggests that the model has a relatively robust ability to predict the PFS of advanced NSCLC patients treated with ICIs. The calibration plots shown in Figure 3H indicated that the probabilities of our prognostic model agreed with the accuracy probabilities on acceptable scales (the dashed lines in the calibration plots correspond to a 10% margin of error).
The mutation status of ARID1A or ARID1B is associated with the TMB level, PD-L1 expression and the TIME modulation of NSCLC
Based on the research above, we reasonably deduced that ARID1A or ARID1B mutation serves as a novel biomarker for ICIs treatment and could have a connection with factors that are proven to be associated with sensitivity to cancer immunotherapy. As shown in Figure 4A, ARID1A or ARID1B mutations were associated with a higher TMB value (ARID1A: 16.2 versus 9.3, P=0.001; ARID1B: 17.1 versus 9.4, P=0.020) and a higher proportion of PD-L1-positive cells (ARID1A: 38.9% versus 12.9%, P=0.040; ARID1B: 41.3% versus 12.4%, P=0.020) in advanced NSCLC patients. Figure 4B reveals the relationships between the TIME with the expression of ARID1A or ARID1B. As shown in the figure, ARID1A or ARID1B expression was related to immunosuppression in 517 lung adenocarcinoma (LUAD) samples and 501 lung squamous cell carcinoma (LUSC) samples, which is mainly characterized by significant reductions in the abundances of activated CD8+ T cells and activated dendritic cells (DCs). This result suggested that ARID1A or ARID1B deficiency might modulate the TIME via the activation of the antigen presentation process and cellular immunity and thus contribute to the change in the sensitivity to ICIs treatment.