On March 16, the melanoma research team from the Department of Dermatology and the Clinical Research Center for Personalized Cancer Immunotherapy of Xiangya Hospital, Central South University published a research paper entitledADORA1 inhibition promotes tumor immune evasion by regulating the ATF3-PD-L1 axisonCancer Cell(IF 23.9), a top international journal. Both the first authors, Professor Liu Hong and postdoc Kuang Xinwei, and corresponding authors, Professor Chen Xiang and Professor Liu Hong, are from the Department of Dermatology of Xiangya Hospital. This research revealed for the first time the molecular mechanism of regulating tumor PD-L1 via ADORA1-ATF3 axis, brought up a new strategy of effectively treating melanoma with the combination of an ADORA1 antagonist and a PD-1 monoclonal antibody (mAb), and identified a reliable screening method for assessing PD-1 mAb therapy efficacy. Such original research results are of profound significance to the diagnosis and treatment of melanoma patients.
Melanoma research team from the Department of Dermatology of Xiangya Hospital
Teaching-clinical research ward round
Melanoma is a serious form of skin cancer that results from the abnormal proliferation of melanocytes and the most lethal among all types of skin cancers. It can occur in the skin, mucous membranes and uvea, and is highly invasive, metastatic and recurrent. In China, the most common clinical types of skin melanoma are acral melanoma and mucosal melanoma, and its morbidity rate grows rapidly by 3-5 percent each year. The two-year survival rate for patients with advanced skin melanoma is 15%, and the five-year survival rate 5%. Thus it is highly malignant.
Apart from treatments such as traditional surgery, interferons, conventional chemotherapy and targeted therapy, revolutionary progress has been made in recent years in the treatment of melanoma with the immune checkpoint blockade therapy focusing on blocking the interaction between programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). In 2018, the Nobel Prize in Physiology or Medicine was awarded to scientists who discovered cancer therapy with immune checkpoint inhibitors. Immunotherapy has been widely used in the clinical treatment of several solid tumors, such as skin tumors, lung cancer, colorectal cancer, and breast cancer. However, the results of more intensive research have shown that the overall response rate of this kind of immunotherapy is less than 40%, and the lack of an assessment strategy for effectively screening melanoma patients for immunotherapy is a knotty problem in clinical practice. Therefore, it is urgently needed to explore the molecular mechanism of immune escape resulting in no response to PD-1 mAb therapy, establish an efficient strategy for screening patients for effective immunotherapy, and develop a new therapy that can increase the response rate of patients.
Adenosine is the core metabolite of adenosine triphosphate (ATP), an organic compound that provides energy to drive many processes in living cells. The level of adenosine, an important endogenous signaling molecule, may be affected by several factors, including ecto-5′-nucleotidase (CD73), adenosine deaminase (ADA), the equilibrative nucleoside transporter (ENT) family, and key transcription factors that regulates the above molecules, such as the hypoxia-inducible factor (HIF1A). Adenosine can combine with four types of G protein-coupled receptors (ADORA1, ADORA2A, ADORA2B, and ADORA3) as ligand to help regulate several physiological and pathological processes such as programmed cell death, cell proliferation, vasodilatation, cardiac rhythms and inflammation, making it a hotspot in current research.
In this research, the team of Professor Chen Xiang used gene editing, targeted interventions with small molecule compounds, high-throughput sequencing and biological information analysis to first reveal that suppressing ADORA1-cAMP axis can regulate the expression level of the key transcription factor ATF3 in melanoma cells, upregulate PD-L1 expression and accelerate the exhaustion of CD8+T cells, thus promoting immune escape. Functionally, they proved via preclinical study that ADORA1 antagonist can enhance the efficacy of PD-1 mAb treating immune-competent mouse models with tumors including melanoma. By retrospectively analyzing the tumor tissue samples of patients receiving PD1 mAb therapy taken prior to the treatment, they found that the response rates of patients whose tumor tissues have lower ADORA1, higher ATF3, and higher PD-L1expressions are higher and prognosis better.
The publication of this paper is the result of the long-term efforts of the melanoma research team of Xiangya Hospital led by Professor Cheng Xiang. The team has long been dedicated to basic research and clinical diagnosis and treatment of skin tumors, and took the lead in establishing the Skin Tumors Research Center of the Chinese Society of Dermatology of the Chinese Medical Association and the Skin Tumors Committee of the Chinese Dermatologist Association. It holds the Xiangya Skin Tumor Forum regularly each year and carries out popularization of knowledge about skin tumors and trainings for grass-roots physicians. In 2019, the team established the Xiangya International Melanoma Research Union together with top scholars from the United States, Australia, Japan, and South Korea. It will put more effort into clinical practice and scientific research of skin tumors to increase its international influence and promote the development of first-class medical disciplines.
