MEDICINE AND HEALTH

New study reveals the mechanism of immunosuppressive microenvironment formation in pancreatic cancer


Immunotherapy has been shown to be effective in a variety of solid tumors. However, for pancreatic cancer, which has the title of “king of cancer”, immunotherapy has not been effective. Recently, Professor Yu Xianpu, Dean of Fudan University Cancer Hospital, and Shi Si, Associate Professor of Pancreatic Surgery, released a study that found for the first time that cysteine-rich protein 1 (CRIP1) plays a key role in the shaping of pancreatic cancer immunosuppressive microenvironment, filling the gap in the field of pancreatic cancer immunosuppressive microenvironment research and providing a theoretical basis for precision immunotherapy for pancreatic cancer patients.

The study showed that CRIP1 can promote bone marrow-derived suppressor cell activation. Based on this mechanism, the research team used an inhibitor to enhance the efficacy of immunotherapy for high-expression CRIP1 pancreatic cancer and confirmed the theoretical feasibility of precision immunotherapy for pancreatic cancer patients. The results were published online in Gastroenterology.

Yu Xianpu is undergoing surgery. Photo courtesy of interviewee

The “immune microenvironment” became a breakthrough

Pancreatic ductal adenocarcinoma is the main type of pancreatic cancer, accounting for about 90% of pancreatic cancers. Due to the high degree of malignancy and poor treatment effect, pancreatic ductal adenocarcinoma has always been one of the most malignant tumors.

In recent years, the rapid development of surgical techniques and comprehensive treatment levels has not brought significant improvement to the prognosis of patients with pancreatic ductal adenocarcinoma. Among them, immunotherapy represented by immune checkpoint inhibitors has shown obvious efficacy in many solid tumors, but the treatment effect of pancreatic ductal adenocarcinoma has not been satisfactory.

What causes people with pancreatic ductal adenocarcinoma to not benefit from immunotherapy? Previous studies have shown that pancreatic ductal adenocarcinoma tumor cells are highly heterogeneous, have inherent characteristics leading to immune evasion, and play a huge role in shaping the immunosuppressive microenvironment through genetic changes and downstream pathways interacting with other cells, which is likely to be the “culprit” of poor immunotherapy. Therefore, the mechanism of action of tumor cells in the shaping of the immune microenvironment of pancreatic ductal adenocarcinoma was explored. Therefore, finding solutions to improve the tumor microenvironment and screening people who can benefit from immunotherapy is very critical for the precise treatment of patients with pancreatic ductal adenocarcinoma.

Discover the key “keys”

How can we effectively discover the key to activating the immune response in pancreatic cancer? The team of Professor Yu Xianpu and Associate Professor Shi Si carried out research on the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma through tissue mass spectrometry imaging system, RNA sequencing, cell mass spectrometry flow cytometry and multiplex immunohistochemical fluorescence staining.

Previous studies have found that the expression of CRIP1 in tumor tissues is significantly increased compared with normal pancreatic tissue, and it is closely related to the invasion of immune cells in pancreatic cancer. In pancreatic ductal adenocarcinoma tissues with higher levels of CRIP1 expression, bone marrow-derived suppressor cells (MDSCs) had higher levels of infiltration, while other cells had lower levels of infiltration. In addition to this, the depleted state and immunosuppressive state of T cells are more common. In terms of mechanism, CRIP1 and conjugates promote their nuclear translocation by entering protein-dependent, promote transcriptional function and induce tumor cells to secrete chemokines, thereby contributing to the infiltration of MDSCs in tumor tissues.

Reveal the mechanism of formation

In further animal experiments, experimental results of mouse pancreas in situ transplantation tumor models showed that CRIP1 can promote MDSC infiltration in tumors by mediating the formation of an immunosuppressive microenvironment, and inhibit the infiltration of a type of T cell and activation of antitumor immunity.

During the experiment, the scheme of combining immunodrugs to improve the tumor microenvironment was explored by using the mouse pancreatic in situ transplantation tumor model, which promoted the invasion of cytotoxic T cells into the tumor in the transplanted tumor overexpressing CRIP1, which significantly slowed down the tumor growth of the mice. At the same time, in pancreatic transplant tumors that overexpress CRIP1, inhibitor combination therapy can effectively activate the anti-tumor immune response.

“This study addresses the dilemma of poor treatment outcomes in pancreatic cancer patients, and discovers for the first time through a series of studies the key role of CRIP1 in shaping the immunosuppressive microenvironment of pancreatic cancer.” Yu said, “This provides a theoretical basis for the combination of antibodies and inhibitors in the clinic, making it possible for pancreatic cancer patients to benefit from immunotherapy.” (Source: China Science News, Zhang Shuanghu, Huang Xin)

Related paper information:http://dx.doi.org/10.1136/gutjnl-2022-329349



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