Early breast tumor deregulates the immune system in lymph nodes, causing metastases later

09-03-2022

Breast cancer often spreads to the lymph nodes or the lungs. But the exact mechanisms that lie behind these metastases in a particular organ are currently still unclear.

Researchers from the Karin de Visser group from the Netherlands Cancer Institute and Oncode have discovered that breast tumors mobilize specific immune cells in the lymph nodes from a distance at an early stage of tumor development, which will eventually lead to metastases in the lymph nodes. This specific mechanism has not been observed in the lungs.

Breast cancer patients with metastases in the lymph nodes tend to face a worse prognosis than patients with clean lymph nodes. The researchers are hoping that their new fundamental insights could lead to new immunotherapies that can fight metastases in the lymph node early on.

The way in which primary tumors drive the immune system plays a vital role in the later development of metastases, as has previously been shown by Karin de Visser’s research group. Her group primarily focuses on the relationship between breast cancer and the immune system.

Group member Kevin Kos has now shown how a primary breast tumor mobilizes regulatory T cells early on in its development, which will eventually lead to the occurrence of metastases in the lymph nodes.

These cells, often referred to as T_regs, are highly immunosuppressive, which prevents the immune system from attacking healthy cells. In many people with autoimmune disorders, like MS or diabetes, these cells are deregulated.

Kos: “It would be beneficial for a tumor to take control of this type of cell. This is currently being investigated, although most studies focus on processes in the tumor or metastasis itself. We were interested in all the changes that occurred during the development of a breast tumor.”

Kos investigated what happened with these T_regsduring the development of a breast tumor in the lymph nodes, lungs, spleen, and blood of a mouse model that he tracked for eight months during the process of developing breast cancer from the very beginning.

“At a very early stage in the development of the tumor, we already noticed all sorts of things change in the body,” Kos explains. “Even before the primary tumor presented in the breast gland we were measuring higher levels of T_regsin the blood. They also looked a bit different and were activated from a distance, which makes these immunosuppressant cells more active than the ones in a healthy mouse.”

The second important and surprising discovery was the observation that this effect was highly localized; it only occurred in the lymph nodes. These hyper-activated T_regs suppressed the natural killer cells found in the area. Those cells are an important aspect of the immune system that can detect and destroy intruders. “As long as they’re allowed to do their work, of course,” Kos says.

Interestingly, research with clinical data sets had previously connected the presence of T_regs to lymph node metastases in breast cancer, Kos knows. “But no one ever elaborated on these results. We are trying to uncover this connection further.”

Together with Tanja de Gruijl’s research group at the Amsterdam UMC, the NKI group proceeded to investigate lymph nodes that had been removed from breast cancer patients with and without metastases, as well as healthy lymph nodes from preventive mastectomies in carriers of hereditary breast cancer genes. These lymph nodes displayed the same phenomenon as the T_regs in mice.

However, the T_regs found in the lungs – another location in which metastases often occur – did not attack natural killer cells. “We currently do not know why,” Kos says. “Although we have our theories. But every organ seems to have its own mechanism. How these mechanisms behind metastases differ between the organs, and what role the immune system plays, will be a new field of research.”

This discovery is currently not very useful in the clinic, Kos states. “The system is way too complex for that. But we do know that breast cancer patients with lymph node metastases have a much lower five-year survival rate. The more you know about the processes during this early stage, the better you can learn to influence it.”

Publication: Kevin Kos et al., ‘Tumor-educated T_regs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche’, Cell Reports, March 1, 2022. DOI: 10.1016/j.celrep.2022.110447.