CD8A and HAPLN3 expression profiling to reveal an immunologic subtype of bladder cancer with favorable survival.

Abstract

e15193 Background: At present, immune checkpoint inhibitors (ICI) have demonstrated robust anti-tumor activity with a favorable safety in bladder cancer (BLCA). However, less than half of BLCA patients respond to immunotherapy. We aimed to further delineate the immunologic subtype of BLCA to pick patients who might benefit from ICI treatment. Methods: The RNA-seq and clinical data were collected from The Cancer Genome Atlas (TCGA) data portal (n = 408) and Gene Expression Omnibus (GEO) (GSE48075, n = 142; GSE32894, n = 308). TCGA and GSE48075 cohort are the discovery datasets, and GSE32894 cohort is used for validation. According to the expression of every specific gene ( Gi), patients were divided into two groups using median FPKM as cutpoint value, namely Gi_high and Gi_low, respectively. Combined with CD8A expression, all the patients were divided to four groups as follows: CD8A_high/ Gi_high, CD8A_high/ Gi_low, CD8A_low/ Gi_high, and CD8A_low/ Gi_low. Then we calculated the pearson correlation coefficients between Gi and 13 immune checkpoint genes ( CD274, IDO1, CTLA4, LAG3, CD276, VTCN1, CD70, HAVCR2, CD40, CD47, TNFRSF18, TIGIT, and TNFSF14). Overall or disease free survival of the four groups were compared using the survfit function from the survival R package and P values from log-rank tests were reported. Results: In the discovery cohort, we found CD8A_high/ HAPLN3_low group showed the best overall survival, whereas the CD8A_low/ HAPLN3_high showed the worst (TCGA, p = 0.013; GSE48075, p = 0.012). Additionally, HAPLN3 was positively correlated with 5/13 immune-checkpoint genes: CD274, IDO1, CTLA4, LAG3, HAVCR2 (r > 0.6, p < 0.01). And the same observations were extended in the validation cohort (GSE32894): CD8A_high/ HAPLN3_low group exhibited a favorable survival (p = 0.00059), and HAPLN3 had a strong correlation with the same 5 immune-checkpoint genes (r > 0.6, p < 0.01). Conclusions: The combination of high CD8A and low HAPLN3 expression identified a subtype of BLCA patients with favorable survival and these findings may further help refining the selection of BLCA patients for immunotherapy.