Colorectal cancer (CRC) ranks as the third most prevalent malignant tumor worldwide. Surgery, chemotherapy and radiotherapy have been the first choice for treatment of CRC for a long time. Therapeutic targeting of immune checkpoint molecules has generated substantial excitement for the treatment of several solid tumors such as melanoma and lung cancer. However, for CRC, only about 15% patients benefit from immune checkpoint blockade (ICB) treatment. The lack of CD8+ T cell infiltration, defining as "immune desert", is one of the important reasons for the ICB therapy failure in CRC’s treatments. Finding a way to overcome "immune desert" may provide new possibilities for CRC patients benefiting from ICB therapy.
In a study published in Science Translational Medicine (IF = 17.9) on January 5th of 2022, a joint team in Chinese Academy of Medical Sciences which led by HUA Fang from the Institute of Materia Medica and ZHANG Hai-zeng from the Cancer Hospital revealed a novel mechanism of TRIB3 in promoting immune evasion in CRC. SHANG Shuang, an assistant researcher of the Institute of Materia Medica, YANG Yu-wei and CHEN Fei, postgraduates of the Institute of Material Medica, are the co-first authors. This article has also been selected by the Editor as the Cover Story of the January issue.
Prof. HUA Fang has long been studying on the tumor promoting mechanism of oncoprotein Tribbles homolog 3 (TRIB3). Her team’s previous work confirmed that TRIB3 is highly expressed in CRC. TRIB3 maintains the cancer stemness by upregulating Wnt/β-catenin signaling activity and promotes the occurrence and development of CRC ( Gastroenterology , 2019). However, it is unclear whether TRIB3 is involved in the regulation of immune evasion of CRC.
In this study, the researchers confirmed that TRIB3 inhibits the transcriptional activity of STAT1 to reduce the expression of chemokine CXCL-10. Such effect inhibits the recruitment of CD8+ T cells and promotes the immune evasion of CRC. These evidences suggest that TRIB3 may be an attractive target to “turn up the temperature” on immunologically cold tumors. Such findings promoted the researchers to explore the reasons for inducing high expression of TRIB3 in CRC. They confirmed that acetylation of TRIB3 by P300 inhibits TRIB3 ubiquitination and degradation. High glucose microenvironment is a metabolic factor leading to active acetylation modification. Combining the clinical diabetic CRC samples and diabetic CRC mouse models, the researchers provide a new mechanism to interpret why diabetic patients showing high incidence and poor prognosis of CRC from the perspective of immune microenvironment. Furthermore, using C646, a specific inhibitor of P300, to reduce the expression of TRIB3 significantly sensitize the therapeutic efficacy of immune checkpoint inhibitors (PD-L1 and PD-1 monoclonal antibodies).
The two CRC studies on TRIB3 suggested that targeting TRIB3 not only reduce the stemness of tumor cells, but also activate the anti-tumor immune response. The development of TRIB3 specific inhibitors is a promising way to achieve the effect of "killing two birds with one stone" in the treatment of CRC.
This paper is dedicated to the memory of Prof. HU Zhuo-wei (1955–2021), a respected pharmacologist and a great teacher! We appreciate his invaluable suggestions and support.