On October 17, “Cell Reportage Medicine” published a new achievement by Yu Xianpu, professor of pancreatic surgery at Fudan University Cancer Hospital, and Shi Si’s team in the form of a cover article. The team found that after receiving neoadjuvant therapy, the pancreatic cancer status changed from “cold” to “hot” and from “sugar” to “fat”; In addition, targeting CD36 (leukocyte differentiation antigen 36), a key molecule of metabolic immunity that is upregulated after neoadjuvant therapy, can significantly improve the therapeutic effect of pancreatic cancer. This reveals the role and mechanism of neoadjuvant therapy at the microscopic level of pancreatic cancer, and confirms that targeting CD36 can significantly promote anti-tumor immunity and have a synergistic effect with standard neoadjuvant treatment regimens to inhibit pancreatic cancer.
Yu Xianpu at work. Photo courtesy of interviewee
Pancreatic cancer is a highly malignant digestive system tumor, with a 5-year survival rate of only 10%, so it is known as the “king of cancer”. Surgery is currently the only way to cure pancreatic cancer, but the overall surgical effect is not satisfactory.
“Surgery combined with postoperative adjuvant therapy is the standard treatment modality for resectable pancreatic cancer. However, in recent years, more and more studies have shown that the comprehensive treatment that was originally placed after surgery is carried out earlier to the preoperative period, which is expected to achieve better surgical results. Yu said that this anti-tumor treatment before pancreatic cancer surgery is called preoperative neoadjuvant therapy. Neoadjuvant therapy has been widely recognized and used in the treatment of borderline resectable pancreatic cancer and resectable pancreatic cancer with high risk factors.
From the perspective of treatment effect, preoperative neoadjuvant therapy can downgrade pancreatic cancer and further improve the radical curative of surgery. However, from the perspective of the mechanism of action, there is still a lack of systematic research on what changes preoperative neoadjuvant therapy brings to pancreatic cancer and what impact these changes have on pancreatic cancer.
In order to elucidate this mechanism of action, Yu Xianpu and Shi Si’s team carried out a series of studies. Through protein-transcriptome sequencing and bioinformatics analysis of pancreatic cancer tissues newly treated with albumin-bound paclitaxel combined with gemcitabine (AG) regimen, the team found that the genes upregulated after neoadjuvant therapy were associated with longer overall survival in pancreatic cancer patients. This suggests that in addition to surgical benefits, neoadjuvant therapies can also benefit patients from a microscopic molecular biology perspective.
At the same time, by molecular typing of samples, it was found that after neoadjuvant therapy, the proportion of molecular subtypes of pancreatic cancer changed from “cold” to “hot”, that is, “immune fever”. The results of single-cell spatial transcriptome sequencing and histochemical staining also indicated that the proportion of CD8+ T cells and TCR clonal expansion was upregulated in the neoadjuvant treatment group.
In addition, combined with the results of metabolomics sequencing and metabolic flow experiments, it was found that the state of pancreatic cancer after neoadjuvant therapy changed from “sugar” to “lipid”, that is, the level of glycolysis was significantly reduced, while the ligand oleic acid of fatty acid receptor CD36 was upregulated.
Therefore, the research team believes that the upregulation of CD36 may be a compensatory metabolic tributary produced by pancreatic cancer under chemotherapy pressure, providing energy support for tumor cells. If this stream is blocked, it is possible to improve the efficacy of neoadjuvant therapy for pancreatic cancer. In further research, the team confirmed this hypothesis through organoid models and animal experiments that targeting CD36 can significantly promote anti-tumor immunity and synergistic with AG protocols to inhibit pancreatic cancer progression.
“This study reveals the mechanism of action of neoadjuvant therapy for pancreatic cancer, and provides a new strategy of AG combined with CD36 monoclonal antibody for neoadjuvant therapy of pancreatic cancer.” “It is worth noting that although this study is based on findings after neoadjuvant therapy, the findings can be generalized to a larger population such as advanced metastatic pancreatic cancer,” Shith said. ”
In the future, the research team will conduct clinical trials to verify the efficacy of AG combined with CD36 monoclonal antibody regimen in patients with pancreatic cancer at different stages. (Source: China Science News, Zhang Shuanghu, Huang Xin)
Related paper information:https://doi.org/10.1016/j.xcrm.2023.101234