In October 2021, Professor Ma Teng's team from the Cancer Research Center of Beijing Chest Hospital affiliated to Capital Medical University published a suppressive role in the immune landscape in molecular oncology journal Molecular Cancer online titled "Profiling of DNA damage and repair pathways in small cell lungcancer reveals " research paper (IF:27.4). The study found that the DNA repair protein RAD51 plays an important role in the immune microenvironment of small cell lung cancer. Inhibition of RAD51-mediated homologous DNA pairing and strand exchange can increase the expression of immune checkpoint-related molecules and the migration of patients' peripheral blood mononuclear cells, further demonstrating the potential of DNA damage repair inhibitors combined with immune checkpoint inhibitors for the treatment of small cell lung cancer. Jin Renjing and Assistant Researcher Liu Bin, graduate students of the Cancer Research Center of Beijing Chest Hospital, are the co-first authors, and Professor Ma Teng is the corresponding author.
Small cell lung cancer is the most deadly pathological type of lung cancer, accounting for about 20% of all lung cancers, and is an aggressive, high-grade neuroendocrine tumor characterized by short doubling time, rapid growth and early metastasis and spread, with a low 5-year survival rate. The mainstay of treatment for small cell lung cancer includes platinum-based chemotherapy and radiation therapy, but the vast majority of patients develop resistance after treatment. Although immunotherapy has been used in patients with small cell lung cancer, the degree of benefit is not high, and the efficacy is only slightly higher than 10%. The suppressive immune microenvironment of small cell lung cancer is an important reason hindering the efficacy of immunotherapy, and its specific mechanism is not clear.
Evidence has been shown that DNA damage repair genes are abnormally expressed in small cell lung cancer cells. Mutations in dna damage repair pathways increase in patients with small cell lung cancer after treatment. Abnormal DNA damage repair pathways are closely related to tumor mutational burden. Total exon sequencing suggests that the subtype of small cell lung cancer with germline mutations is effective for treatments that target DNA repair. PARP inhibitors and the like can activate the body's innate immune system through interferon-activated gene STING (stimulator of interferon genes), and then cooperate with PD-1/PD-L1 immune checkpoint treatment to kill tumors. The research team systematically explored the relationship between DNA damage repair and the immune microenvironment of small cell lung cancer, and found that the homologous DNA pairing and chain exchange links in the homologous recombinant repair of DNA double-strand breaks were negatively correlated with the immune microenvironment of small cell lung cancer. Inhibiting RAD51-mediated DNA pairing and strand exchange leads to an increase in cytoplasmic dsDNA release after DNA damage, thereby activating the inherent immune signaling pathway of cGAS-STING, promoting the expression of immune checkpoint-related molecules and the migration of peripheral blood mononuclear cells in patients, or in conjunction with immune checkpoint therapy regimens, playing an active role in immunotherapy for small cell lung cancer. The project was funded by the Beijing Municipal Health Commission's Lung Cancer Project (2020-2022).
Ma Teng, Researcher, Professor, Doctoral Supervisor, Beijing Chest Hospital/Beijing Institute of Tuberculosis Thoracic Tumors Affiliated to Capital Medical University. He has been engaged in basic and applied basic research on DNA damage repair for a long time, and has undertaken two national natural science foundation projects, and has been selected as a beijing overseas high-level talent project and a specially appointed expert in Beijing. He has published several high-level papers as a first author or corresponding author in journals such as Molecular Cell, Cell Death & Differentiation, Signal Transduction and TargetedTherapy. He is also a guest editor of Frontiers in Cell and Dimensional Biology magazine.