TN breast cancer: the dangerous links between stromal, immune and tumor cells
Understanding cancer also requires the study of its close environment. This is being constantly demonstrated by Fatima Mechta-Grigoriou, Inserm Research Director, head of the Stress and Cancer team (Institut Curie/U 830 Inserm/team certified by Ligue Nationale Contre le Cancer - the French national league against cancer). Tumor cells are not isolated within the organism. They interact with their healthy neighbors and even use them for their purposes. Among them, fibroblasts are support cells that form the framework of all the tissues. They can be activated by signals released by the tumor cells. They are known by the generic name of "cancer-associated fibroblasts" (CAF). CAFs make up the most abundant cell population present in the core of tumors, mixing with the tumor cells.
Each cancer sub-type has its own CAFs
“CAFs help create an environment that fosters the development of cancer,“ explains the researcher. “Different ones exist according to the signals that the cancerous cells have activated in them, but until now we had no idea of the impact of this diversity.” In samples of tumor tissue taken from women with breast cancer, Fatima Mechta-Grigoriou’s team showed that there are 4 sub-types of CAF. To do this she developed an innovative technique to analyze the combination of 6 different markers on these cells. Although breast cancer patients present all 4 CAF sub-types, their proportion varies according to the different types of breast cancer.
- CAF-S2 and CAF-S3 most resemble normal cells and are the least activated; they are predominant in luminal A breast cancers
- CAF-S4 are the most common in HER2+ cancers, which are cancers that respond to herceptin
- In triple negative cancers, we find mainly CAF-S1 or CAF-S4
So-called “triple negative” cancers account for 15% of all breast cancer cases, but they are difficult to treat. There is no targeted therapy known to date and a large number of these cases respond poorly to immunotherapy. One of the reasons for this resistance could be the accumulation of CAF-S1. “Their presence leads to a chain of reactions in the immune system cells, creating an immuno-depressive environment, in other words rendering the immune system deficient,” explains Fatima Mechta-Grigoriou. CAF-S1 inhibit the anti-tumor activity of the immune system, which could explain the ineffectiveness of the antibodies which target the PD1/PD-L1 signaling pathway, and which today give us great hope for the future of immunotherapy. These molecules tasked with “restoring” the immune system to enable it to attack cancer cells could be blocked by CAF-S1. The next step for Fatima Mechta-Grigoriou and her team would therefore be to deactivate CAF-S1 to make these treatments effective in women with triple negative breast cancer.
Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, Sirven P, Magagna I, Fuhrmann L, Bernard C, Bonneau C, Kondratova M, Kuperstein I, Zinovyev A, Givel AM, Parrini MC, Soumelis V, Vincent-Salomon A, Mechta-Grigoriou F.
Cancer Cell. 2018 Feb 12. pii: S1535-6108(18)30011-4. doi: 10.1016/j.ccell.2018.01.011.