Quantitative MHC class-I/-II gene expression levels inCDK12mutated prostate cancer reveal intratumorally T cell adaptive immune response in tumors

AbstractBackgroundThe inactivation of Cyclin-dependent Kinase 12,CDK12, has been used as a predictive biomarker of treatment response to immune-checkpoint blockade (ICB) in advanced prostate cancer (PCa). However, some patients with CDK12 alterations fail to respond to ICB. Changes in MHC expression have been linked to tumor progression and reduced response to ICB in different malignancies.MethodsUsing transcriptome and WES data from primary (n=48) and metastatic (n=10)CDK12defective PCa; we investigated variation in the expression of the MHC genes and associated downstream changes. We divided the tumors into “High” and “Low” expression levels of MHC-I and -II based on gene expression quartiles.ResultsCDK12defective tumors with increased MHC levels showed the activation of several pathways associated with the immune system and elevatedPD-L1, IDO1, andTIM3expression. There was also increased composition of CD8+ T cells, B cells, γδ T cells, and M1 Macrophages inCDK12mutated tumors with elevated MHC levels. In contrast,CDK12defective tumors with decreased MHC expression were often subject to loss of heterozygosity (LOH) genomic events affecting MHC-I/-II and theHLAgene cluster on chromosome 6.ConclusionsOur data suggest thatCDK12defective PCa express higher levels of classical MHC and have an active and inflamed tumor microenvironment with elevated immunomodulatory pathway expression and increased presence of effector T cells. The finding of lower MHC expression in tumors with LOH of associated genes on chromosome 6 suggests reduced MHC expression may be caused by acquisition of specific somatic genomic events that reduce the expression of these antigen presentation genes. Collectively, these data indicate that implementing a combined measure ofCDK12mutation and MHC expression levels together with an evaluation of LOH status may better predict outcomes for prostate cancer tumors classified as eligible for ICB treatment.