CDK12/13 inactivation triggers STING-mediated antitumor immunity in preclinical models
Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan
Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan
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Research Article Cell biology Oncology

CDK12/13 inactivation triggers STING-mediated antitumor immunity in preclinical models

Abstract

Inactivation of cyclin-dependent kinase 12 (CDK12) defines an immunogenic molecular subtype of prostate cancer characterized by genomic instability and increased intratumoral T cell infiltration. This study revealed that genetic or pharmacologic inactivation of CDK12 and its paralog CDK13 robustly activates stimulator of interferon genes (STING) signaling across multiple cancer types. Clinical cohort analysis showed that reduced CDK12/13 expression correlates with improved survival and response to immune checkpoint blockade (ICB). Mechanistically, CDK12/13 depletion or targeted degradation induced cytosolic nucleic acid release, triggering STING pathway activation. CDK12/13 degradation delayed tumor growth and synergized with anti–PD-1 therapy in syngeneic tumor models, enhancing STING activity and promoting CD8+ T cell infiltration and activation within tumors. Notably, the antitumor effects of this combination required STING signaling and functional CD8+ T cells. These findings establish STING activation as the key driver of T cell infiltration and the immune-hot tumor microenvironment in CDK12-mutant cancers, suggesting that dual CDK12/13 inhibitors and degraders activate antitumor immunity and potentiate responses to immunotherapies.

Authors

Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan

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Figure 1

CDK12/13 inactivation or low expression levels are associated with elevated STING activation and improved response to ICB.

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CDK12/13 inactivation or low expression levels are associated with elev...
(A) Analyses of 10× Genomics Visium spatial transcriptomics on CDK12 mutant versus wild-type (WT) metastatic castration-resistant prostate cancer (mCRPC) samples. Top: Enrichment of the indicated pathways in tumor cells. Middle: Representative images illustrating the enrichment of STING activity signature in tumor areas. Bottom: The top 10 pathways enriched by gene set enrichment analysis (GSEA), utilizing the MSigDB Hallmark database, in tumor cells. Type I and II IFN responses are highlighted in red. Adj., adjusted. Scale bar: 200 μm. (B) Association between expression of CDK12/13 and STING activity signature in the indicated cancer types. Data were acquired from The Cancer Genome Atlas datasets. Abbreviations are defined in the legend of Supplemental Figure 1. (C) Association between pretreatment expression of CDK12/13 and overall survival in the indicated cohorts treated with ICB therapy. MI-ONCOSEQ: a pan-cancer cohort at the University of Michigan. The KM plotter data were acquired from the KM plotter database (https://kmplot.com/analysis/). (D) Association between pretreatment expression of CDK12/13 and ICB response in the melanoma and MI-ONCOSEQ ICB cohorts in C. (E) Single-cell RNA sequencing assessing expression of indicated genes or signature in tumor cells in ICB-treated cohorts. Left: Expression of CDK12/13 in tumor cells in patients with favorable versus unfavorable clinical outcomes. Right: Expression of STING activity signature in tumor cells in patients with favorable versus unfavorable clinical outcomes. Data were acquired from published research articles (see Methods). Low expression of CDK12/13 was defined as the bottom 20th percentile within each cohort. Two-tailed t tests were performed in B (with Bonferroni’s correction) and E, log-rank tests in C, and Fisher’s exact test in D. Panels B and D show box-and-whisker plots with the median (center line), 25th–75th percentiles (box), 10th–90th percentiles (whiskers), and outliers beyond the whiskers.