Lung cancer is the malignant tumor with the highest incidence and mortality rate in China, and lung adenocarcinoma, as its main pathological type, has great clinical value and translational potential for exploring the detailed molecular mechanisms in this type of patients. In recent years, "polymorphic microbiome" has been listed as a major new feature of cancer, which has contributed to a major breakthrough in human knowledge of cancer. Although the existence of intratumoral fungal microbiome has been confirmed, there is insufficient evidence at the molecular and cellular levels to demonstrate the origin of intratumoral fungi and their association with tumor development. 

Based on this, Prof. Peng Zhang's team from the Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, in collaboration with Prof. Hui Wang/Ningning Liu's team from the School of Public Health, School of Medicine, Shanghai Jiaotong University, and Prof. Changbin Chen's team from Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences (CAS), have published an article online in the leading international oncology journal, Cancer Cell, titled " The intratumor mycobiome promotes lung cancer progression via myeloid-derived suppressor cells".

In this study, the clinical samples of patients with confirmed lung adenocarcinoma were used, and based on fluorescence in situ hybridization (FISH), ITS amplicon sequencing and macro-genome sequencing, it was demonstrated that there was a significant disturbance of the fungal microenvironment and an enrichment of A. sydowii in the tumors of the patients with confirmed lung adenocarcinoma, and a clinical isolate of A. sydowii was isolated and cultured from the tumor tissues of the patients with confirmed lung adenocarcinoma using culture genomics techniques. sydowii clinical isolate (Figure 1).

Figure 1. Intratumor mycobiome dysbiosis was correlated with LUAD pathology and identified a highly abundant live fungus

To verify the specific mechanism of A. sydowii in promoting lung adenocarcinoma progression, the research team validated the promotion of the fungus in lung cancer progression using a subcutaneous tumor model, a lung in situ tumor model, and a KrasLSL-G12D/+/P53 fl/fl lung spontaneous model, and verified that the fungus promoted the progression of lung cancer through β-glucosylation in the cell wall by using scavenging antibodies as well as in knockout mice. A. sydowii induces the expression of CARD9 signaling pathway in macrophages by binding Dectin-1 to β-glucan in the cell wall, promotes the secretion of IL-1β to recruit downstream MDSCs, and enhances its ability to inhibit the killing of CD8+ T-cells, and ultimately induces the formation of an immunosuppressive microenvironment, thus promoting the development of lung cancer. The correlation between A. sydowii and the immunosuppressive microenvironment of patients' tumors was also verified in this study with the help of multicolor immunofluorescence and fluorescence in situ hybridization, using pathological sections of lung adenocarcinoma patients' samples, and it was finally confirmed that the enrichment of A. sydowii in tumors was closely related to the poorer prognosis of patients with lung adenocarcinoma (Fig. 2).

Figure 2. A. sydowii binds Dectin-1 via β-glucan in the cell wall, induces the expression of CARD9 signaling pathway in host cells, promotes the secretion of IL-1β to recruit downstream MDSCs cells and enhances their immune-suppressive ability, and ultimately induces the formation of an immune-suppressive microenvironment, thereby promoting lung cancer development.

This study provides more solid evidence to support the polymorphic microbiome as an additional biological feature of cancer, and fills some of the gaps in the study of the molecular mechanisms of fungal microbiome in lung cancer. In terms of clinical translation, this study provides the idea of precisely targeting fungi at the strain level to promote intratumoral immunocide against tumors, which will greatly promote the process of individualized treatment strategies for lung cancer based on targeting fungi.

Link to original article：https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00288-X