Research Highlights
Identification of a new target for sensitizing tumors to immune checkpoint blockade

Immune checkpoint blockades targeting PD-1/PD-L1 or CTLA4 have revolutionized the current cancer therapy paradigm based on their high durability. However, only a small subset of cancer patients shows response. Thus, there is an unmet need for developing therapeutic strategies that could enhance the response rate to Immune checkpoint blockades. 

Dr. Ruey-Hwa Chen’s group identifies a critical role of the deubiquitinating enzyme TRABID in suppressing anti-tumor immunity. Mechanistically, TRABID is upregulated in mitosis and governs mitotic cell division by removing K29-linked polyubiquitin chain from Aurora B and Survivin, thereby stabilizing the entire chromosomal passenger complex. TRABID inhibition causes micronuclei through a combinatory defect in mitosis and autophagy and protects cGAS from autophagic degradation, thereby activating the cGAS/STING innate immunity pathway. Genetic or pharmacological inhibition of TRABID promotes anti-tumor immune surveillance and sensitizes tumors to anti-PD-1 therapy in preclinical cancer mouse models. Clinically, TRABID expression in most solid cancer types correlates inversely with an interferon signature and infiltration of anti-tumor immune cells. Together, this study identifies a suppressive role of tumor-intrinsic TRABID in anti-tumor immunity and highlights TRABID as a promising target for sensitizing solid tumors to immunotherapy.

This work is mainly contributed by postdoctoral fellow Dr. Yu-Hsuan Chen and research assistant Mr. Han-Hsiun Chen. Other authors include Assistant Research Fellow Dr. Kuen-Phon Wu and scientists in National Yang Ming Chiao Tung University and Taipei Medical University. The study has been published in Nature Communications.

Article title: “TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation.”

Article link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10220035/

Authors: Chen YH, Chen HH, Wang WJ, Chen HY, Huang WS, Kao CH, Lee SR, Yeat NY, Yan RL, Chan SJ, Wu KP, Chen RH*