Fight against the “most toxic” breast cancer with a precise “scout”

Breast cancer is currently the most common malignant tumor in women. Among them, triple-negative breast cancer accounts for about 15% of the total breast cancer population, and is known as the “most toxic breast cancer” because of its high degree of malignancy, short survival time of patients, and lack of effective treatment targets. In recent years, a number of clinical trials have confirmed that immunotherapy represented by PD-1/PD-L1 inhibitors is a promising treatment for triple-negative breast cancer, but some patients are still difficult to benefit from this therapy. How to accurately screen and treat effective populations and further improve the efficacy of triple-negative breast cancer immunotherapy is a difficult problem that needs to be solved clinically.

On May 17, the team of Shao Zhimin and Jiang Yizhou, professors of Fudan University Cancer Hospital, published a cover paper in Cell Press’ medical journal Med, revealing for the first time a cell subpopulation called “CCL19+ dendritic cells” that plays a key role in the immunotherapy process of triple-negative breast cancer. This provides a new direction for solving the problem of precision immunotherapy for triple-negative breast cancer.

Schematic illustration of dendritic cell action. Photo courtesy of interviewee

For the first time, the key role of “dendritic cells” was revealed

Triple-negative breast cancer is more complex than other subtypes of breast cancer, and treatment strategies are more difficult to formulate. Clinical studies have found that even with the use of cutting-edge immunotherapies such as PD-1/PD-L1 inhibitors, there are still some patients who are difficult to benefit.

On the basis of deep cultivation of precision treatment of breast cancer and the first “Fudan classification” of triple-negative breast cancer, the team of Shao Zhimin and Jiang Yizhou carried out a series of clinical trials, which increased the treatment efficiency of triple-negative breast cancer by 3 times. In recent years, the research team has continuously deepened the “Fudan typing” from multiple perspectives such as protein, metabolism, immunity, and microorganisms, and explored new therapeutic targets to break through the therapeutic bottleneck of some triple-negative breast cancer subtypes.

The tumor microenvironment is the “soil” for tumor survival, and finding key cell subsets in it to improve the efficacy of precision therapy is an important direction for breast cancer treatment. As one of the most important innate immune cells, dendritic cells play a “scout” role in the tumor microenvironment. However, at present, there is still a lack of systematic research on which dendritic cell subsets are most important and can be accurately targeted immunotherapy.

To this end, the team revealed for the first time a cell subpopulation called “CCL19+ dendritic cells” by analyzing the “first-hand” single-cell sequencing data from clinical trials, which plays a key role in the treatment of triple-negative breast cancer that affects the efficacy of immunotherapy. Multiple independent clinical trials have confirmed that this cell infiltration in the tumor microenvironment can suggest that immunotherapy is effective in patients with triple-negative breast cancer. Follow-up studies have found that after infusing this group of cells into the body, the efficacy of PD-1 monoclonal antibody can be multiplied, significantly inhibiting tumor growth.

Why are CCL19+ dendritic cells so efficient? Based on a large-scale patient cohort, tumor tissue analysis of fresh patients, and multiple staining of paraffin sections, the researchers found that CCL19+ dendritic cells are a group of mature cell subsets with efficient immunomodulatory ability, and the immunokilling ability is highly activated in tumors with such cells.

In vivo experiments have found that the reinfusion of CCL19+ dendritic cells can activate CD8+ T cell function. The mechanism exploration found that these dendritic cells affected CCR7+ memory T cells through the key functional molecule CCL19, and then played a synergistic effect with immunotherapy, while the combined use of CCL19 and PD-1 monoclonal antibody could further promote the tumor killing effect of T cells and activate the anti-tumor immunity of triple-negative breast cancer. Therefore, CCL19-based treatment modalities can be used as a potential therapeutic strategy to improve the efficacy of immunotherapy for triple-negative breast cancer.

Precision immunotherapy enables “non-invasive stratification”

Dendritic cells play such an important role, so how can they be used to benefit more patients with triple-negative breast cancer? The researchers used large-scale paired triple-negative breast cancer paired tumors and peripheral blood samples to conduct the study, and found that the level of CCL19 in the tumor was significantly positively correlated with the level of CCL19 in the peripheral blood circulation. Through multiple clinical trials, the researchers found that not only the level of CCL19 in the tumor is correlated with the efficacy of immunotherapy, but also the level of plasma CCL19 can predict the efficacy of immunotherapy.

“For advanced triple-negative breast cancer, 80% of patients with high peripheral blood CCL19 can achieve significant tumor retraction, while less than 35% of patients with low CCL19 can achieve significant tumor retraction.” Wu Songyang, co-first author of the paper and breast surgery at Fudan University Cancer Hospital, said, “The detection of peripheral blood CCL19 by enzyme-linked immunosorbent detection technology is expected to realize non-invasive monitoring of immunotherapy patients, achieve dynamic prediction of efficacy, timely adjust treatment plans, and improve patient prognosis.” ”

Jiang Yizhou said that the current tumor diagnosis and efficacy testing mainly rely on invasive tissue biopsy, which is not only traumatic to patients, but also time-consuming and expensive. Non-invasive liquid biopsy that collects relevant information such as peripheral blood can achieve simple, non-invasive, rapid and low cost, overcoming the two major pain points of insufficient predictive efficiency of previous markers and the need for invasive tissue biopsy, which is expected to effectively improve the treatment effect of triple-negative breast cancer and reduce the medical and economic burden of patients.

In previous clinical trials based on “Fudan classification”, the research team used the targets found in basic research to increase the treatment efficiency of first-line treatment of patients with metastatic triple-negative breast cancer to the current international high of 81.3%, realizing the “closed loop” of the whole chain from basic to clinical. In the immunotherapy non-invasive detection protocol developed by the research team, only 1 ml of blood needs to be drawn, and after half an hour of analysis, a report can be issued. At present, the relevant research has applied for invention patents.

“This will guide the more precise implementation of immunotherapy for patients with triple-negative breast cancer.” Jiang Yizhou said, “This study based on the key cell subsets of the tumor microenvironment will add new flame to breast cancer immunotherapy and help formulate the ‘Chinese plan’ with the ‘Fudan Results’.” ”

The study was also highly praised by journal reviewers and was considered to have “strong innovation and very important clinical application value”, and was selected as the highlight discussion of the 45th San Antonio Breast Cancer Congress (SABCS, one of the largest, highest level and most influential international academic conferences in the field of breast cancer in the world) in 2022. (Source: China Science News, Zhang Shuanghu, Huang Xin)

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