Through a process that resembles seeding plants, cancer cells break away from a primary tumor and travel through tissues until they find fertile breeding grounds that will support their growth. Once cancer spreads, there are few effective treatment options.1 For example, even though diagnostic and therapeutic advances have increased breast cancer survival rates, metastatic disease remains the leading cause of death for these patients.2 Despite this devastating track record, very little is known about the mechanisms that underlie cancer metastasis.3
The human body is equipped with various defense systems to prevent metastasis, but some tumors can influence a tissue’s immune response so that it instead supports cancer seed germination. Scientists now take a closer look at tumor-immune cell crosstalk to identify the molecules and cell types that act as fertilizers and prepare tissues for the arrival of circulating tumor cells.
In a recent paper published in Cell Reports, Karin de Visser, group leader at the Netherlands Cancer Institute and the Oncode Institute and professor at Leiden University, described a regulatory T cell (Treg) population that is reprogrammed by cancer cells to reduce the immune system’s ability to prevent metastasis.4 Because this population selectively promotes lymph node metastasis, de Visser’s findings reveal how tissue-specific interactions between tumor and immune cells may determine which tissue a cancer cell homes to, offering important clues for precision medicine approaches to treat the disease.
To better understand how cancer cells reorganize a pre-metastatic niche, de Visser and colleagues first took a close look at the immune cells that populate commonly invaded organs in various breast cancer mouse models. “One of the most obvious changes we saw was that Treg [numbers] were increased in the circulation and in every organ we looked at, sometimes even at early cancer stages when the [primary] tumor was still very small,” de Visser said.
Tregs are part of the body’s safety mechanism to prevent autoimmunity by modulating natural killer (NK) and T cell activity. In their mouse models, de Visser and her team found that the population of brainwashed Tregs that localize to lymph nodes were hyperactivated and impaired NK cell function, likely to help cancer cells stay hidden from the immune system in this tissue.
The scientists next depleted Tregs and found that this prevented lymph node metastasis but did not alter cancer spread to other organs. “It was mind-blowing, because these cells carry the genetic instructions to develop breast cancer and metastasize, so it really showed that this [tissue specificity] is not a cancer cell-intrinsic process, they need help from other cells,” de Visser said.
To understand if Tregs also control metastatic spread in humans, de Visser next collaborated with researchers at the Vrije Universiteit Amsterdam and studied the immune cell populations in tumor and lymph node biopsies of breast cancer patients and healthy controls. Similar to their mouse models, the scientists found elevated Treg and reduced NK cell levels in cancer patients compared to healthy controls. Moreover, patients with early-stage lymph node metastasis showed even higher Treg levels, correlating with a stronger reduction in NK cell numbers. “This is the first and strongest evidence to show that Tregs can selectively promote metastasis to lymph nodes but not [to] the lung,” said Wanjun Chen, chief of the mucosal immunology section and senior investigator at the National Institute of Dental and Craniofacial Research who was not involved in the current study.
In the clinic, doctors currently treat metastatic disease the same way regardless of which tissues are affected. “Our studies show that a personalized approach with different [therapeutic] strategies depending on where the metastasis is located may work better, but we still need a lot of follow up studies in different models, focusing on different immune subpopulations to really get a better understanding of the different immunosuppressive mechanisms that are at play in different organs,” de Visser concluded.
- O.S. Blomberg et al., "Immune regulation of metastasis: mechanistic insights and therapeutic opportunities,” Dis Model Mech, 11(10): dmm036236, 2018.
- H. Dillekas et al., "Are 90% of deaths from cancer caused by metastases,” Cancer Med, 8(12): 5574–5576, 2019.
- A.I. Riggio et al., "The lingering mysteries of metastatic recurrence in breast cancer,” Br J Cancer, 124(1):13-26, 2021.
- K. Kos et al., “Tumor-educated T regs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche,” Cell Rep, 38(9):110447, 2022.