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bioRxiv · 10.1101/2022.06.16.496429

Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer

Kandala, S.·Voith von Voithenberg, L.·Chocarro, S.·Ramos, M.·Keding, J.·Brors, B.·Imbusch, C.·Sotillo, R.
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Abstract

Chromosomal instability (CIN), the inability to correctly segregate chromosomes during cell division, is a common characteristic of solid tumors. CIN contributes to tumor evolution by promoting intratumor heterogeneity, thus facilitating resistance to cancer therapies. In vitro studies have demonstrated that cells with complex karyotypes are recognized and eliminated by natural killer (NK) cells. Paradoxically, it has also been observed that human tumors with high levels of CIN have an immunosuppressive phenotype. It remains unclear which CIN-associated molecular features alter immune recognition during tumor evolution. Previous studies with Polo-like kinase 1 (Plk1) overexpression in Her2-positive breast tumors, resulted in increased levels of CIN and delayed tumorigenesis. Using this mouse model, we show that high CIN tumors activate a senescence-associated secretory phenotype (SASP) and become immune evasive by activating RELB signaling and upregulating PD-L1 in a non-cell-autonomous manner. Single-cell RNA sequencing of immune cells from early-stage induced mammary glands revealed that macrophages, NK cells, B cells and regulatory T cells are programmed to a suppressive phenotype during tumor development. In human tumors, we further establish the importance of RELB/p38 signaling in understanding the interplay between CIN and the immune system, highlighting the need for novel adjuvant therapies in the context of chromosomally unstable tumors.

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Kandala, S., Voith von Voithenberg, L., Chocarro, S., Ramos, M., Keding, J., Brors, B., Imbusch, C., Sotillo, R.. 2022-06-17. Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer. https://doi.org/10.1101/2022.06.16.496429

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