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Why can't tumor cells be completely killed?

Is there a more precise cancer treatment approach?

This is a global medical researcher

Major problems that have been tried to be solved over the years

Institute of Biomedical Sciences, Fudan University

Luo Min, Lu Zhigang, Gao Hai team

Jointly with Chinese Academy of Sciences Molecular Cell

Zhao Yun's team at the Center for Scientific Excellence and Innovation

Discovery of a novel, highly functionally conserved tumor immunosuppressive receptor CD300ld

Potential for tumor immunotherapy

New ideal target

Further improving the effectiveness of tumor treatment

The research results were published in Nature magazine

Recently selected as Fudan University 2023

“Top Ten Scientific and Technological Advances”

Discover new targets for tumor treatment.

Let immunotherapyMore accurate, safe and effective

Human medical technology is constantly developing and many diseases can be cured, but at present, there is still no cure for cancer.

As early as a hundred years ago, people tried to treat tumors by stimulating the immune system. It was not until about 20 years ago that they discovered that T cells (one of the main components of immune cells) can kill tumor cells. However, the therapeutic effect of activating T cells through various means has always been limited.

"What 'weapons' do tumor cells use to resist T cells? Are there any targets or loopholes in this 'weapon' that can allow us to destroy it?"Six years ago, Luo Min, who had just arrived at Fudan University, began to think about this problem.

Immune checkpoint blockade therapy is a revolutionary advance in the field of tumor treatment in recent years. It activates the immune system to attack tumor cells by blocking the signal transduction pathway between tumor cells and immune cells. However, this therapy can only produce effects in about 20% to 30% of tumor patients, and the proportion of long-term benefits is even lower.

Myeloid cells are one of the "culprits" that lead to the poor effect of this therapy - the tumor immune microenvironment contains a large number of myeloid cell populations that suppress immunity, which play a key role in tumor development and treatment tolerance.

As an important "weapon" for tumor cells to resist the action of T cells, do myeloid cells have a "weakness"?Luo Min's team conducted in-depth research on myeloid cell targets, trying to find out the secret of how it resists immunotherapy.

The team selected 356 receptors specifically expressed on myeloid cells and constructed a mouse tumor model for screening. Using gene editing technology, they knocked out specific receptors at specific locations, observed the distribution of knocked-out myeloid cells inside and outside the tumor, and determined which receptors the tumor preferred through comparison.

After multiple rounds of experimental screening,One target, called CD300ld, stood out. When it was knocked out, myeloid cells were significantly reduced in the tumors.Not only that, this target has another important feature:Specifically expressed on neutrophils.

Targeting CD300ld can reverse the tumor microenvironment and inhibit tumor development

Neutrophils play an important role in tumor anti-immunotherapy, but there is no neutrophil-specific drug target. The specificity of CD300ld expression means high safety and conservativeness of treatment.

“Broadly expressed targets may exist in a variety of cells, so, chemotherapy or radiotherapy will result in "killing one thousand enemies and injuring eight hundred of your own". We are now developing targeted therapy in the hope of "killing only the enemy and not hurting yourself" - only killing bad cells and not hurting good cells.Luo Min explained.

Moreover, the CD300ld target also showed effective anti-tumor properties. The team tested multiple cancer types on mice and achieved a tumor growth inhibition rate of more than 50%.

Twenty years of dedicated research,

“Will studyConversionFor medicineThe greatest driving force

Luo Min graduated from Peking University with a bachelor's, master's and doctoral degree in cell biology. More than 20 years ago, she was determined to solve the major human diseases:"I hope that what I study can eventually be applied clinically and have a role to play on patients. This is so meaningful to me!"

During her doctoral studies, Luo Min mainly studied HIV and explored how to block the binding of the virus and receptors through drugs. Continuing with this idea, she is still studying how to block the pathway between tumor cells and the human immune system through vaccines.

"I still want to devote myself to basic research." After graduating with a doctorate, Luo Min worked at the Centers for Disease Control and Prevention for three years before deciding to return to academia. During her research at the Southwestern Medical Research Center in the United States, she found that the mechanisms of chronic diseases such as HIV and tumors in onset and immune escape were very similar, and began to study the use of vaccines to treat tumors with immunotherapy. Today, this research result has been approved by the FDA and entered the clinical testing stage.

In 2018, she and her husband Lu Zhigang joined the Institute of Biomedical Sciences of Fudan University. Luo Min chose this place as a new career starting point because she valued the dual advantages of basic research and applied transformation of Fudan Shanghai Medical College.

"There are many research institutes near Fudan University School of Medicine, and there are rich academic exchanges. In addition, there is an affiliated hospital next door, which makes it very convenient for us to learn about clinical conditions from doctors, which is conducive to later drug transformation," she said.

Starting from scratch. As a young researcher, Luo Min admits that this process is not easy. Six years later, Luo Min and Lu Zhigang's laboratory has more than a dozen people, forming an academic family with clear division of labor, unity and love.

Group photo of team members

"You have to be 200% prepared to do scientific research." Luo Min can no longer remember how many difficulties he encountered in the past six years. When focusing on analyzing the CD300ld receptor, they spent nearly a year doing experiments to identify which group of myeloid cells it works on.

Despite this, Luo Min is not in a hurry to achieve disruptive results in the short term. When she was a student, she often marveled at how terrible it was to spend 20 years on a single research project. But now she is calm and composed."In fact, it is very common to spend 20 years studying a problem."

Her goal is already clear: in the next few "five years", she will concentrate on studying tumor immunity and continue in this direction.

Taking basic research as the guide,

drawThe galaxy of receptor-ligand interaction networks

"Basic research is the forerunner. Only when the entire blueprint of a receptor is made clear and the target is understood deeply enough, the mechanism of drug development will be clearer." In Luo Min's view, the article published in Nature last year was just the first step. It is far from enough to reveal the functional orientation and expression spectrum of the CD300ld target. She will continue to study the upstream and downstream of this target and other receptors.

At present, Luo Min’s team is working on multiple fronts in parallel.On the one hand, we need to study the signal regulation network of CD300ld target in cells, answering the question "which ligand does it bind to and what intracellular signal does it transmit, allowing neutrophils to suppress immunity."

On the other hand, we actively try drug transformation and cooperate with companies to develop antibodies.Luo Min plans to advance the transformation process to the pre-clinical trial stage through the laboratory system he has built.

Graduate students in the team are analyzing flow cytometry data

In the long run, Luo Min has a bigger goal:Build a large platform covering the interaction network of more than 8,000 cell surface receptors.

She used an analogy, "The interaction between receptors and ligands is like a conversation between people. Through this process, cells are told what to do, which leads to a series of subsequent events." By building a platform that accommodates more than 8,000 proteins, she tried to answer which receptors each cell interacts with in different situations, leading to changes in cell fate.

The application prospects of this platform are self-evident. The idea of ​​many biomedical research today is to screen out a target with the strongest response from a bunch of ligands, which is highly dependent on specific scenarios. If the entire blueprint can be drawn, the network around different cells in any scenario can be depicted. Researchers only need to observe which interactions are enhanced or weakened, and they can select dozens of drug targets for verification, thereby greatly improving scientific research efficiency.

In fact, the study of the ligand spectrum of CD300ld targets is just a small part of this grand plan."It's a star in this platform, and we want to know what the whole galaxy looks like, and then we can pick the stars."Luo Min currently finds it difficult to estimate how long it will take to build a complete platform, but they are advancing at a rate of several hundred proteins per year, and “one day we will definitely be able to complete the map.”

"The effectiveness of immunotherapy is increasing step by step, from less than 5% in the past to more than 10% now. I hope our work can take this work to the next level."No matter what, Luo Min hopes that one day her research will eventually be transformed into clinically used drugs and contribute to saving the lives of cancer patients.

This research was supported by the National Natural Science Foundation of China, the National Key R&D Program, and the Shanghai Science and Technology Major Projects. Wang Chaoxiong, Zheng Xichen, and Zhang Jinlan are the co-first authors of the paper, and Luo Min, Zhao Yun, Lu Zhigang, and Gao Hai are the corresponding authors of the paper.

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