New Target for Cancer Immunotherapy: President Mien-Chie Hung’s International Research Team Published Their Study in Nature Communication
Date：February 4, 2021
A significant progress in Taiwan’s cancer immunotherapy research! The international research team led by CMU President Mien-Chie Hung found that “Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy.” This study was published in the prestigious journal Nature Communication, which provided a new insight for cancer immunotherapy. Furthermore, the Nature Research Cancer Community of the United States invited President Hung’s team to share about their research motivation, ideas, and experiences behind this study, indicating that the international medical community pays great attention to this new research finding.
“Immunotherapy is different from traditional chemotherapy, radiotherapy, and molecular targeted therapy. Immunotherapy does not kill the tumor directly, it is a new treatment that can overcome the immune suppression of the patients and restart the patients’ own immune cell to kill tumors,” explained President Hung.
Generally speaking, when T cells are activated, it can kill cancer cells. However, over-activation can cause autoimmune diseases. To avoid over-activation, T cells will express inhibitory receptors (ex. PD-1 and TIM3) and these inhibitory receptors will bind to their ligands to inhibit the immune activation of T cells when immune response is not required. In contrast, cancer cells will also express corresponding ligands (ex. PD-L1) to interact with PD1 when fighting T cells, in order to inhibit T cells from killing cancer cells. Moreover, cancer cells can release Gal-9, the ligand of TIM3, to bind with TIM3 on T cells and cause death to T cells. Both PD-1 and TIM3 on T cells have the function of inhibiting T cell activity, and blocking the inhibitory ability of PD-1 and TIM3 receptors on T cells has become the main direction for developing anti-cancer drugs.
In addition, this study found that PD-1 can bind to Gal-9, and antagonizing the death of T cells induced by the binding of Gal-9 and TIM3. That is, the “triple alliance” of PD-1, Gal-9, and TIM3 allows T cell to survive, however lost the ability to kill cancer cells.
To restore the cancer-killing activity of T cells, the research team used activated antibodies to stimulate GITR, the “co-activated receptor” of T cells, so that the T cells can regain their cancer-killing ability. This combined therapy of activated GITR antibody and inhibitory Gal-9 antibody greatly increases the number of T cells with tumor killing activity, and the tumor growth is inhibited significantly.
Previous research have shown that a large amount of interferon would be produced during the process of activation of immune system. This study further found that the combined effect of β interferon and γinterferon will significantly increase the expression and secretion of Gal-9, meaning that the increased expression and secretion of Gal-9 in immunotherapy may be one of the reasons that adaptive resistance occurs in immunotherapy. Therefore, blocking Gal-9 and combining other immunotherapy might overcome the adaptive resistance.
This study revealed that the immune checkpoint protein PD-1 has a new biological function in regulating the death of T cells, clarified the regulation mechanism of Gal-9 expression and secretion in tumor microenvironment, and discovered the anti-tumor efficacy of the combination of Gal-9 as a new immunotherapy target and other immunotherapy. This study provided a new direction and prospect for future cancer immunotherapy.