Scientists discover special immune cells stop metastatic cancer

Metastatic disease, when cancer spreads from the primary tumor to other parts of the body, is the cause of most cancer deaths. Although researchers understand how cancer cells escape from the primary site to spawn new tumors, it is not well understood why some of these rogue cancer cells spawn new tumors, sometimes decades later, while others do not. don’t do it.

Now, a research team from the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center (MECCC) has discovered a natural immune mechanism in mice that prevents escaped cancer cells from developing into tumors elsewhere in the body. The results were published in the journal Cell. The study is titled “Lung Resident Alveolar Macrophages Regulate the Timing of Breast Cancer Metastasis.”

“Preventing or curing metastasis is the most critical challenge in cancer,” said Julio Aguirre-Ghiso, Ph.D., study leader and director of the Cancer Dormancy Institute at MECCC. “We believe our findings have the potential to point toward new therapies to prevent or treat metastatic disease.”

The study’s co-first authors are Erica Dalla, Ph.D., a former student, and Michael Papanicolaou, Ph.D., a postdoctoral researcher in Dr. Aguirre-Ghiso’s lab.

The role of dormancy in cancer

Cells that migrate from primary tumors and metastatic germ cell tumors are called disseminated cancer cells (DCC). Some DCCs behave aggressively, immediately triggering tumors in new tissues, while others remain in a state of suspended animation called dormancy.

“How some DCCs can stay in tissues for decades and never metastasize has been a mystery for a long time, and we think we have found the explanation,” said Dr. Aguirre-Ghiso, also a professor of cell biology, Oncology and Medicine and the Rose C. Falkenstein Chair in Cancer Research at the Albert Einstein College of Medicine.

Breast cancer and many other types of cancer metastasize to the lungs. In research involving three mouse models of metastatic breast cancer, Dr. Aguirre-Ghiso and colleagues determined that when breast cancer DCCs spread to the lungs’ air sacs (alveoli), they are kept in a dormant state by immune cells called alveolar macrophages.

Overview of the immune system

“Alveolar macrophages are the lung’s first responders, defending the organ against bacteria and dangerous substances like environmental pollutants,” said Dr. Aguirre-Ghiso. These specialized macrophages, he notes, appear early in embryonic development and reside in lung tissue throughout life.

“Our results demonstrate a new role for these macrophages, in which they recognize and actively interact with DCCs and, by secreting a protein called TGF-β2, produce signals in cancer cells that keep them in a dormant state,” explains Dr. Aguirre-Ghiso said.

“Since each organ in the body has its own set of tissue-resident macrophages, they may also function to control DCCs in these organs. Our study showed for the first time that these specialized macrophages function to actively induce dormancy in the DCCs.

Confirming the importance of alveolar macrophages in maintaining dormant DCCs, Dr. Aguirre-Ghiso and his team found that their depletion in mice significantly increased the number of activated DCCs and subsequent metastases in their lungs compared to mice with normal levels of immune cells.

As DCCs become more aggressive, the researchers found, they become resistant to pro-dormancy signals produced by alveolar macrophages. Ultimately, this escape mechanism allows some DCCs to “wake up” from dormancy and reactivate to form metastases.

“Understanding how immune cells control DCCs could lead, among other strategies, to novel anti-metastatic cell therapies,” said Dr. Aguirre-Ghiso. For example, he noted, it might be possible to boost macrophage signaling so that DCCs never awaken from dormancy or find ways to prevent older DCCs from becoming resistant to macrophage signaling. dormancy.