By studying for the first time the effects of chemotherapy on certain cells in the tumor microenvironment [1] , a team from the Institut Curie and Inserm, led by Dr. Fatima Mechta-Grigoriou, has taken a major step towards understanding the mechanisms of chemotherapy resistance in ovarian cancer patients. Indeed, the scientists have succeeded in identifying a population of fibroblasts (support cells) capable of inhibiting the antitumor action of certain immune cells even after treatment. Published in Nature Communications, these results pave the way for potential anti-cancer therapeutic applications.
Around 70% of ovarian cancers are "high-grade serous" [2], with a severe prognosis. Optimizing treatments and developing new strategies are therefore major scientific and medical challenges. Today, scientists are focusing on a specific cell population: fibroblasts, heterogeneous cells present throughout the body in connective tissue (which holds other body tissues together). Cancer-associated fibroblasts (CAF) help to maintain the tumor microenvironment, considered to be an important driving force in the development of the disease (e.g. by promoting the spread of metastases). Understanding the role and evolution of CAFs during disease and its treatment is therefore essential to finding more effective therapeutic approaches against cancer.
The effect of chemotherapy on cancer-associated fibroblasts
Within the Cancer, Heterogeneity, Instability and Plasticity unit (Inserm, Institut Curie), the team led by Dr. Fatima Mechta-Grigoriou [3] , evaluated the effect of chemotherapy treatment on four CAF populations previously identified in high-grade serous ovarian cancers. The researchers were able to distinguish several categories of CAF: some were beneficial, blocking tumor development, while others were harmful, contributing to cancer growth. The scientists observed that a significant proportion of harmful CAFs are inactivated following chemotherapy treatment. However, a variable proportion of these harmful CAFs remain activated despite chemotherapy, with an impact on treatment efficacy.
CAFs and the immune system
The team wanted to go a step further and looked at the interaction between these harmful CAFs and the immune system. Their results reveal that the population of harmful CAFs blocks the anti-tumor activity of essential immune cells: CD8+ T lymphocytes. Targeting these residual harmful CAFs, in combination with chemotherapy, could therefore improve the prognosis of ovarian cancer patients.
" These results suggest that a therapeutic approach specifically targeting these residual harmful CAFs, in addition to chemotherapy, could increase the anti-tumor activity of CD8+ T lymphocytes and improve cancer treatment and patient prognosis," explains Dr. Fatima Mechta-Grigoriou. " At the Institut Curie, we are currently conducting the which focuses on these same CAF populations to combat metastasis and treatment resistance in triple-negative breast cancers."
Fibroblasts beyond cancer
Recently published results [4] by the same team have also highlighted the role of fibroblasts in the development of chronic kidney disease, a major cause of mortality worldwide. By accumulating, these fibroblasts induce kidney dysfunction. Scientists have shown that the presence of specific fibroblasts at diagnosis is predictive of a poor prognosis in the patient.
" The various fibroblast populations are involved at different stages of pathological development in cancer, but also appear in new and intriguing ways in other pathologies, considerably broadening our field of research ," concludes Dr. Fatima Mechta-Grigoriou.
The tumor microenvironment is defined as the set of cells or biological constituents (blood vessels, immune cells, fibroblasts, signaling molecules, extracellular matrix) located around cancer cells and interacting strongly with them.
[1] The tumor microenvironment is defined as the set of cells or biological components (blood vessels, immune cells, fibroblasts, signaling molecules, extracellular matrix) located around cancer cells and interacting strongly with them.
[2] High-grade serous ovarian cancer is a subtype that develops from epithelial cells.
[3] The Stress and Cancer team at the Institut Curie is headed by Dr. Fatima Mechta-Grigoriou, an outstanding research director at Inserm.
[4] Cohen et al, 2024, WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease, Nature Communications, 2024 Jan 25;15(1):743. doi: 10.1038/s41467’024 -44886-z.
