Dendritic Cells and Cancer: Insights from Dr. Elly Marcq at VUB
Imagine your body as a large kitchen, and health as a perfectly baked cake. In that kitchen work numerous chefs, that is, cells that monitor the quality of ingredients, temperature, and the preparation process. Their task is to prepare the cake flawlessly, but sometimes saboteurs sneak into the kitchen. Tumors are the ones that try to change the recipe, add wrong ingredients, and disrupt the process. Dendritic cells (DC) are the main chefs who recognize the bad ingredients, i.e., tumor cells, and teach the other chefs, T cells, how to remove them.
However, as in any complex kitchen, not all chefs are equal. There are several types of dendritic cells, each with its own function. Some are specialized in activating CD8+ T cells, the “sous-chefs” who directly attack tumor cells. Others, like cDC2 cells, can be flexible: sometimes they help activate CD4+ helper T cells, which oversee the process and coordinate the kitchen work, but sometimes, under the influence of the tumor environment, they become passive or even sabotage the process, allowing “spoiled ingredients” to remain in the body.
The tumor microenvironment acts like a stressful kitchen. Bad factors such as immunosuppressive cytokines, metabolic stress, lack of oxygen, and altered fat metabolism can turn dendritic chefs into passive or even sabotaging variants. The result? Our “cake”, health, suffers.
Activation of Dendritic Cells: Flt3L and CD40 Agonists
Scientists have found ways to “empower the chefs.” One of the key signals is Flt3L, a molecule that increases the number of dendritic cells in the tumor. However, more chefs alone do not mean a better cake, without training, they do not know what to do. That is why Flt3L is often combined with CD40 agonists. The CD40 agonist activates and matures dendritic cells, enabling them to systematically recognize tumor cells and trigger a strong immune response.
Flexibility and Challenges of cDC2 Cells
cDC2 cells are interesting because they can be either active helpers or passive saboteurs. Their behavior depends on complex signals from the tumor microenvironment. We spoke with Dr. Elly Marcq, an expert in tumor immunology at VUB.
cDC2 can be either pro-immunogenic (activating T cells) or immunosuppressive. How do enzymes, and which specific enzymes, influence cDC2 function, and what role do they play in communication with T cells?
Dr. Elly Marcq: In our laboratory, we focus on cell–cell interactions and the heterogeneity of the tumor microenvironment, not on enzymes. This is a completely different research area and requires different techniques. In short, enzymes can regulate cDC2 function in several ways – through metabolic regulation, antigen presentation, and cytokine production. Examples of such enzymes are kinases and proteases.
Flt3L increases the number of dendritic cells in the tumor, but this alone does not reduce tumor growth. Can these limitations be overcome, and what are the main challenges?
Dr. Elly Marcq: Flt3L indeed causes initial ‘priming’ of dendritic cells, but these cells remain immature. Additional activation and maturation are needed to make them functional. That is why Flt3L is often combined with a CD40 agonist – this combination stimulates the activation and maturation of dendritic cells, overcoming these ‘limitations.’
αCD40 therapy uses CD40 agonists to activate dendritic cells, but only some patients respond. What determines the success of the therapy?
Dr. Elly Marcq: The patient’s response depends on the composition of immune cells in the tumor microenvironment. In some patients, there are many T cells that could be activated, but these cells may be ‘exhausted’ and unable to fight the tumor. Interestingly, patients with fewer but more active CD8+ T cells often have a better response. That is why today there is a focus on identifying predictive biomarkers that can show who will respond to therapy. Particularly challenging are tumors with high mutational diversity, such as melanoma.
This shows how successful immunotherapy requires balance because too much activation can cause autoimmunity, and too little allows the tumor to survive.
Studies Highlighting Complexity
Acute myeloid leukemia: the drug candidate may be effective as monotherapy or in combination with standard chemotherapies
Acute myeloid leukemia (AML) is a blood disease in which the bone marrow produces abnormal white blood cells. One of the genes frequently mutated in AML is FLT3, and mutations in it are associated with a more aggressive form of the disease. Since most AML cells carry the FLT3 receptor, scientists have decided to use it as a target for a new therapy. In this research, a drug called FL-Fc-DM1 was developed, which combines a molecule that recognizes FLT3 with the cytotoxic substance DM1. The idea is that the drug precisely finds and destroys only leukemic cells, while healthy cells in the body remain mostly undamaged. FL-Fc-DM1 shows potent activity against AML cells in the laboratory. It is especially important that it acts on cells resistant to the standard drug cytarabine, because it forces them to enter the cell cycle and then induces their death. The FLT3 receptor is also found on progenitors of dendritic cells, which are crucial for immune surveillance and the recognition of foreign or tumor cells.
“Moving forward, we propose a translational roadmap for early-phase clinical development, encompassing preclinical toxicology studies in non-human primates, evaluation of pharmacokinetics and biodistribution, and identification of predictive biomarkers such as FLT3 expression to guide patient selection,” the scientists concluded. The authors come from several institutions across China, the USA, and Hong Kong, including Sun Yat-Sen University in Shenzhen, Guangzhou First People’s Hospital, the University of Oklahoma Health Sciences Center, and the Chinese University of Hong Kong.
PDAC: Flt3L and CD40 Agonist Combination
Immunotherapies targeting T cells have so far failed to significantly slow the progression of pancreatic ductal adenocarcinoma (PDAC). The main reasons are the tumor’s weak ability to be recognized as a threat and its strongly immunosuppressive microenvironment. The study showed that low levels of Flt3 ligand (Flt3L) partly cause cDC deficiency in PDAC. Treatment with a combination of systemic Flt3L and a CD40 agonist restored cDC numbers and function in both mice and patient samples. CD40 activation alone is not sufficient, but in combination with Flt3L, it triggers a strong type I immune response. These findings demonstrate that therapies targeting dendritic cells can enhance the antitumor response in PDAC, overcome the immunosuppressive microenvironment, and pave the way for more effective immunotherapies for pancreatic cancer patients.
The authors come from Washington University School of Medicine in St. Louis, USA, the Departments of Medicine, Pathology & Immunology, Surgery, and Genetics, as well as the McDonnell Genome Institute and the Siteman Cancer Center, and the Medical University of South Carolina in Charleston, including the Department of Surgery and Hollings Cancer Center.
Metastatic colorectal cancer
Metastatic colorectal cancer (CRC) is highly resistant to therapies. Tumors generate local and systemic immunosuppression, which allows cancer cells to evade immune surveillance and to grow and spread throughout the body. Dendritic cells (DCs) play a key role in the recognition of tumor antigens, as well as in their processing and presentation to T cells, which triggers an antitumor immune response. However, tumors develop mechanisms that interfere with DC function, favoring tumor growth, metastasis, and resistance to treatment.
Of particular interest are conventional dendritic cells type 2 (cDC2), which are common in tumors and highly plastic – they can change their appearance and function in response to factors secreted by the tumor. This plasticity affects both the development of antitumor responses and the effectiveness of immunotherapies. The study used a novel 3D co-culture system of cDC2 and tumor organoids obtained from patients to investigate how primary and metastatic CRC alter the phenotype and function of cDC2. The system demonstrated intense interactions between cDC2 and tumor cells. This 3D system holds promise as a platform for testing therapies aimed at preventing or reducing tumor-induced dendritic cell dysfunction. The study provides new and important insights into how CRC alters cDC2 function, which may be key to developing more effective therapeutic strategies.
The authors are from Dutch institutions, including the Department of Medical BioSciences, the Department of Pulmonary Diseases, and the Department of Medical Oncology at Radboud University Medical Center in Nijmegen, as well as the Department of Medical Oncology at Erasmus MC Cancer Institute, University Medical Center Rotterdam.
TPEX cells
Colon cancer and other tumors are often difficult to treat because cancer cells can “escape” the body’s immune system. Immunotherapies help T cells—important cells that attack cancer—perform their job more effectively. Some of these drugs target proteins like PD-1 and LAG-3, which “slow down” T cells, and chemotherapy is often combined with these immunotherapies to make the body more aggressive in attacking tumor cells.
In this study, scientists examined how chemotherapy affects certain T cells inside tumors, called TPEX cells. The authors of this study are affiliated with multiple institutions across Australia, Belgium, and the USA, including the University of Western Australia, Telethon Kids Institute, the University of Pennsylvania, the University of Antwerp, and the Brussels Center for Immunology and VIB Center for Inflammation Research in Belgium.
They found that chemotherapy increased the number of T cells expressing PD-1 and LAG-3. Combining chemotherapy with drugs that block PD-1 and LAG-3 led to a significantly stronger antitumor response than using either drug alone. To completely eliminate the tumor, it was necessary to combine all the treatments—chemotherapy plus both immunotherapies.
This study shows that chemotherapy changes the “behavior” of T cells in tumors. By monitoring these changes, doctors can better decide which immunotherapy to combine with chemotherapy, increasing the chances of effective treatment. The study was conducted in mice.
VSIG4 and Tumor Macrophages
There are special immune cells called tumor-associated macrophages (TAMs). These cells often help tumors grow and spread, and scientists want to discover the molecules that these cells use to make this possible. One of these molecules is VSIG4, which acts as a “brake” on the immune system, slowing down the immune cells’ response against the tumor.
In the study, scientists used publicly available data on human tumors to determine where VSIG4 is found.
The study’s authors are from the Brussels Center for Immunology (BCIM) at Vrije Universiteit Brussel and the VIB Center for Inflammation Research, both located in Brussels, Belgium. Their work spans the Laboratory of Cellular and Molecular Immunology, the Laboratory of Myeloid Cell Immunology, and the Laboratory of Dendritic Cell Biology and Cancer Immunotherapy. They found that VSIG4 expression in human tumors appears mostly in TAMs and may be associated with worse prognosis, though further studies are needed to confirm its role. They then studied the role of VSIG4 in mouse models of tumors. Tumors were grown in normal mice and in mice that do not produce VSIG4 (so-called Vsig4-deficient mice). Interestingly, VSIG4 could not be detected in the tumors in these mice.
The study concludes that mice are not an ideal model for studying the role of VSIG4 in primary tumors because the molecule is almost absent in them. Although VSIG4 in human tumors may be important for tumor growth and poor prognosis, these results cannot be easily applied to mice. Further research is needed to develop better models to understand how VSIG4 affects tumors and the immune response.
Within the complexity lies hope
Dendritic cells play a key role in anti-tumor immunity, but their function depends on the tumor microenvironment, T cell status… Activation of DC, combination of Flt3L and CD40 agonists, targeted immunotherapy, chemotherapy, and checkpoint blockade requires understanding of not just one element. The success of treatment depends on how all the “ingredients” behave together. This complexity explains why immunotherapy sometimes works and sometimes not.
Yet, within this complexity lies hope. Every new study, whether on Flt3L, CD40 agonists, LAG-3, PD-1, or VSIG4, adds another piece to the puzzle, because the main goal is to learn how to empower our immune chefs to recognize, react to, and remove tumors before they sabotage the entire recipe.
Image credit: Dr. Elly Marcq/VUB
These publications were produced as part of the Maria Leptin EMBO Fellowship, which allowed us to spend two months exploring the world of science at VUB in Brussels. Importantly, all articles were the result of our own choice of topics and in accordance with our interests.
