Quantitative MHC class-I/-II expression levels in CDK12 mutated prostate cancer patients reveal intratumorally T cell adaptive immune response in tumors

Treatment of advanced prostate cancer (PCa) remains a therapeutic challenge. The promising improvements provided by new immune-checkpoint blockade (ICB) therapies have shown only modest benefits in a minority of PCa patients. CDK12 defective-PCa is a recently described immune active class of advanced PCa with an elevated mutational burden, high inflammatory levels, and increased immune cell infiltrate. CDK12 has been proposed as a predictive biomarker of treatment response to ICB since partial response treatment has been found among CDK12 PCa patients treated with ICB. This study was designed to investigate the molecular causes of treatment resistance among patients with CDK12 loss-of-function (hemizygous and homozygous loss-of-function) in primary (TCGA-PRAD, n = 48) and metastatic (mCRPC-SU2C, n = 10) PCa. We hypothesize that the expression of the MHC-I and -II genes would differ in the CDK12 defective tumors, which would explain the lack of response in some patients treated with ICB. Using RNA-seq data, we were able to distinguish two groups of tumors with CDK12 defective tumors based on differential MHC expression. Tumors with increased MHC levels showed the activation of several pathways associated with the immune system and elevated PD-L1, IDO1, and TIM3 expression. There was also increased composition of CD8+ T cells, B cells, γδ T cells, and M1 Macrophages in tumors with elevated MHC levels. These data suggest that MHC expression and associated immune response pathways may provide new biomarkers for ICB therapeutic response in CDK12-defective PCa. ### Competing Interest Statement The authors have declared no competing interest.