Impact of CDK12 mutation on immune response in prostate cancer

Author(s)

William Lautert Dutra

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-06-22

Examining board members

Jeremy Andrew Squire; Juliana Meola Lovato

• Advisor: Jeremy Andrew Squire

Abstract

The 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. Using public domain transcriptome and WES data from the primary (n=48) and metastatic (n=10) CDK12 defective PCa, we investigated variation in the expression of the MHC genes and associated downstream changes. Based on gene expression quartiles, we divided the tumors into \"High\" and \"Low\" expression levels of MHC-I and -II. CDK12 defective 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 an increased composition of CD8+ T cells, B cells, γδ T cells, and M1 Macrophages in CDK12 mutated tumors with elevated MHC levels. In contrast, CDK12 defective tumors with decreased MHC expression were often subject to loss of heterozygosity (LOH) genomic events affecting MHC-I/-II and the HLA gene cluster on chromosome 6. Our data suggest that CDK12 defective 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 the acquisition of specific somatic genomic events that reduce the expression of these antigen presentation genes. Collectively, these data indicate that implementing a combined measure of CDK12 mutation 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. (AU)

• FAPESP's process: 21/12271-5 - Impact of CDK12 mutation on immune response in prostate cancer
• Grantee: William Lautert Dutra
• Support Opportunities: Scholarships in Brazil - Master