Researchers find the root of immunosuppression and chemoresistance in TNBC tumors

Researchers find the root of immunosuppression and chemoresistance in TNBC tumors

Researchers find that triple-negative breast cancer tumors (TNBC) gain immunosuppression and chemoresistance through interactions between interleukin 34 and myeloid suppressor cells.

TNBC is a type of breast cancer characterized by the absence of one of the three typical cell surface receptors seen in other breast cancers. TNBC accounts for 15-20% of all breast cancers; It is very aggressive and has a poor prognosis and high relapse rate. Most worryingly, a large proportion of TNBC tumors develop resistance to chemotherapy.

A team of researchers from the Institute of Genetic Medicine (IGM) at Hokkaido University has identified a relationship between a cell signaling protein called interleukin 34 (IL-34) and the development of immunosuppression and chemoresistance in TNBC tumors. Their findings, which identify a novel treatment target for TNBC, were published in the journal Cancer Immunology, Immunotherapy.

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Previous work by the research team had shown that IL-34 is an independent factor for poor prognosis in TNBC. The team decided to study the role of IL-34 in detail to determine how it leads to poor prognosis in TNBC. To do this, they used an IL-34-expressing TNBC cell line, from which they established an IL-34-deficient cell line. They inoculated mice with these cell lines and compared the immune cell populations that infiltrated their tumors.

They found that IL-34 is key to modulating the balance between two populations of myeloid suppressor cells (MDSC). Specifically, within the tumor microenvironment, IL-34 caused a large increase in the population of monocytic MDSCs (M-MDSCs) and a decrease in polymorphonuclear MDSCs (PMN-MDSCs). M-MDSCs are particularly important because they have potent immunosuppressive effects themselves and also differentiate into tumor-associated macrophages that suppress the anti-tumor immune response. Meanwhile, PMN-MDSCs have low immunosuppressive activity and strong angiogenic ability. Based on these backgrounds, they hypothesized that the interaction between IL-34 and MDSCs is responsible for chemoresistance in TNBC tumors.

They showed that a drug that neutralizes IL-34 reduces the growth rate of IL-34-expressing tumors, making them susceptible to the chemotherapy drug paclitaxel, a standard treatment for TNBC. In particular, IL-34-MDSC interaction causes chemoresistance by tipping the tumor interior toward an immunosuppressive state while simultaneously inhibiting angiogenesis, thereby preventing chemotherapeutic agents from reaching the entire tumor. Finally, they analyzed human data from the Cancer Genome Atlas (TCGA) and found a positive correlation between IL-34 and M-MDSCs and a negative correlation between IL-34 and PMN-MDSCs in TNBC tumors - showing that the results from mouse models could be translated to humans.

Our data showed that the combination therapy of IL-34 blockade and chemotherapy drugs was very effective and could be clinically significant.”

Nabeel Kajihara, first author

Source:

Hokkaido University

Reference:

Kajihara, N., et al. (2022) Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer. Cancer immunology, immunotherapy. doi.org/10.1007/s00262-022-03293-3.

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