Professor Huang Bo’s Team Made Advancement in the Immune Mechanism Research on Tumor Dormancy

2018-03-03

On February 12, the Journal of Clinical Investigation published a paper entitled “STAT3/p53 Pathway Activation Disrupts IFN-β-induced Dormancy in Tumor-repopulating Cells” on open access. Associate Researcher Liu Yuying and graduate students - Lv Jiadi and Liu Jinyan from the Institute of Basic Medical Sciences (IBMS) are the co-first authors, Professor Huang Bo as the corresponding author.

 

When the tumor cells in body are attacked by chemotherapeutics, radiotherapy or immune cells, the tumor seed cells with stem property (e.g. queen ant of an ant colony) will convert to the state of dormancy without any response to external attacks, thus surviving the attacks from radiotherapy, chemotherapy and body immunity and becoming the fundamental factor of tumor recurrence and metastasis. Regardless of the significance of tumor dormancy, by far, the research on tumor dormancy is just at the starting point. And tumor dormancy is still an intriguing challenge in tumor research. Huang Bo’s team found previously that, the key antitumor immune factor IFN-γ induces tumor-repopulating cells (i.e. tumor seed cells) in dormancy via the indoleamine 2,3-dioxygenase (IDO)-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway (Nat Commun. 2017 May 10; 8:15207). Based on this, the team has further found that, the key antitumor immune factor IFN-β has a better dormancy induction effect than IFN-γ. On the one hand, IFN-β activates the IDO-Kyn-AhR pathway similarly and induces tumor-repopulating cells to be under dormancy. On the other hand, it further induces tumor seed cells to be under dormancy by inducing serine residue phosphorylation of STAT3. Furthermore, to suppress the IDO-Kyn-AhR pathway enables IFN-β to activate dual the phosphorylation of serine and tyrosine of STAT3. After entering nucleus, it will significantly increase the p53 expression, which will directly inhibit the pentose phosphate pathway of glycometabolism and cytopoiesis of antioxidative NADPH, thus causing that the glutathione of oxidized form cannot convert to the reduced glutathione via NADPH. As the result, free radical cannot be eliminated and the dormant tumor-repopulating cells induced by IFN-β will enter the state of apoptosis. The interpretation of this mechanism provides a new direction for addressing the problem that the dormant tumor seed cells cannot be eliminated clinically at present and develops a new way to the tumor immunotherapy.

 

Currently, the tumor immunotherapy has been applied to clinic cases successfully. Based on the clinical observation for some tumor patients showing better treatment effect such as melanoma patients, some patients suffer tumor recurrence and metastasis after three to five years, which shows that, partial tumor seed cells can convert to the state of dormancy and survive the attack from immune cells. Once the immune environment changes, such tumor seed cells will grow into recurrent or metastatic tumors that are visible clinically. Therefore, targeting dormant tumor seed cells are the key for tumor immunotherapy as well as the core for successful tumor immunotherapy ultimately. And the research results lay a foundation for this.

 

This research was done by Professor Huang Bo’s team and is sponsored by the CAMS’s Medical and Health Science and Technology Innovation Initiative (2016-I2M-1-007) and National Natural Science Foundation of China. Professor Cao Xuetao from IBMS, Professor Hu Zhuowei from Institute of Materia Medica, and Professor Qin Xiaofeng from the Suzhou Institute of Systems Medicine were the investigators in the research.

 

 

(Institute of Basic Medical Sciences)