PAX5 Haploinsufficiency Induces Immune Inhibitory-related Molecules Expressions Of CD8+T Cells In The Tumor Microenvironment

Background:Loss of function of PAX5 plays an important role in PAX5 mutation tumor,and PAX5 haploinsufficiency promoting tumorigenesis is related to immune escape.The mechanisms of PAX5 mutations inducing tumor immune escape has not been clarified.Objective: Using bioinformatics analysis and constructing the cell and mouse model of PAX5 haploinsufficiency to illustrate the potential mechanism of PAX5 mutations concerning tumor immune escape.Methods:We first estimated the proportions of 22 immune cell types and the expressions of immune inhibitory-related molecules based on gene expression profiles(GEPs)from B-acute lymphoblastic leukemia(B-ALL)with PAX5 mutations by CIBERSORT,an established algorithm.Then,we constructed the PAX5 haplodeletion A20 cell lines,built allografted A20 tumor models and evaluated the effect of PAX5 haplodeletion on immune inhibitory-related molecules in the tumor microenvironment(TME).Results:The percentages of T cells in bone marrow of B-ALL with PAX5 mutations were no statistically different from that in bone marrow of B-ALL without PAX5 mutations,except for T cells follicular helper(Tfh).But a variety of up-regulated immune inhibitory-related molecules in bone marrow of B-ALL with PAX5 mutations were identified.By different approaches,we found that several immune inhibitory-related molecules of CD8+ T cells in TME of PAX5 haplodeletion clones such as TIM3,NR4A1 and BATF,were increased significantly compared with that of PAX5 wild type control.The IFN-g of CD8+ T cells in TME of PAX5 haplodeletion tumors was decreased significantly compared with that of PAX5 wild type control.Conclusions:PAX5 haploinsufficiency induced high expressions of TIM3,NR4A1 and BATF in the TME and was involved in CD8+ T cells dysfunction or exhaustion.