Cancer stem cells induce macrophage aging, creating conditions for tumor formation

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Cancer stem cells cause senescence of macrophages in mice with healthy immune systems, creating the conditions for tumor formation.

Cancerous tumors are composed of a mixture of cells, the most important of which are cancer stem cells. These cells are able to evade the immune response and establish new cancerous tumors. Research has focused on identifying biomarkers for cancer stem cells and developing therapies that target these cells. Unfortunately, candidate drugs developed from these efforts have so far not been very effective in clinical trials.

A research team led by Associate Professor Haruka Wada of Hokkaido University’s Institute for Genetic Medicine examined the mechanisms by which cancer stem cells evade the immune system in mouse models. They showed that cancer stem cells induce senescence in macrophages – the immune cells responsible for the first step in destroying cancer cells. Their findings are published Journal for Cancer Immunotherapy.

One of the biggest questions in cancer development is how cancer develops in people with healthy immune systems. Most research on cancer stem cells has been done in vitro or in immunodeficient mouse models, which do not account for a fully functional immune response. The lack of efficacy of cancer stem cell-targeting drugs suggests that the immune response, or lack thereof, is more important than previously thought.”

Haruka Wada, Associate Professor, Institute of Genetic Medicine, Hokkaido University

The team used two glioblastoma tumor cell lines, one of which was capable of inducing tumor formation (cancer stem cells) and the other was not. In mouse models, cancer stem cells suppress the proliferation of macrophages; Further investigation showed that macrophages cultured with cancer stem cells exhibited senescence or cellular senescence. Macrophages were not the only immune cells affected; Although T cell proliferation was unchanged, their antitumor activity was suppressed due to immunosuppressive factors produced by senescent macrophages. The team identified interleukin 6 (IL-6), produced by cancer stem cells, as the molecule responsible for triggering these effects.

The team also demonstrated that supplementing mice with cancer stem cells with a molecule called nicotinamide mononucleotide led to the proliferation of non-senescent macrophages and reduced immunosuppressive factors produced by senescent macrophages, inhibiting tumor growth and increasing mice’s survival time.

“Our results indicate that drugs targeting senescent macrophages could be a treatment for cancer—an unprecedented development,” Wada concluded. “We believe these drugs could be part of a treatment that prevents new onset of tumors, as well as a therapy that prevents recurrence after cancer treatment.” Future work will focus in two ways: confirming that this finding holds true for cancers other than glioblastomas, and confirming that the findings apply to human cancers.


Journal Reference:

Wada, H., etc. (2023). Tumor cell-induced macrophages play a key role in senescence initiation followed by stable growth in the immunocompetent tumor state. Journal for Cancer Immunotherapy.

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