Resistance to immunotherapy: a brand new cellular type involved in the tumor microenvironment
The “Stress and cancer” team (Inserm) at Institut Curie revealed for the first time the existence of a specific population of fibroblasts involved in resistance to immunotherapy. These fibroblasts show no genetic alteration but are characterized by specific markers. They are directly involved in the suppression of immune defenses and prevent immunotherapy from being effective. Recently published in “Cancer Discovery”, this research is also under a patent and a clinical trial is currently being developed at Institut Curie to improve immunotherapy effectiveness in patients.
A large number of different cells making up the tumor microenvironment compose tumors and gravitate around tumor cells. These normal cells do not carry any genetic alteration but play a variety of roles in the pathology of the tumor. Among them, cells from the immune system tend to eliminate tumor cells. These defense cells are stimulated and revitalized by immunotherapies, enabling them to “attack” tumor cells more effectively.
Dr. Fatima Mechta-Grigoriou, Research Director 1 Inserm, Director of the “Stress and cancer” lab at Institut Curie, a team labilized by the Ligue Nationale Contre le Cancer, studies another type of cells present in tumor microenvironment, namely the fibroblasts. These ubiquitous cells, which form a supporting tissue within the body, are among the most abundant ones in the tumor microenvironment, and interact with tumor cells.
“Our work shows that some specific fibroblasts are also able to interact with immune cells and block their defense action. When tumors are enriched in these particular fibroblasts, immune system is much less efficient and immunotherapy can no longer be effective,” explains Dr. Fatima Mechta-Grigoriou.
In this interdisciplinary study, an innovative state-of-the-art technology known as single-cell analysis of the tumors was used, bringing biology, bioinformatics and mathematics skills of the “Stress and cancer” team together with those of clinicians. For the first time, their work reveals the existence of a new sub-types of fibroblasts that deactivate the immune system and prevent it from being revitalized by immunotherapy. If a patient treated by immunotherapy shows high content of these fibroblasts in the tumor, the immunotherapy treatment will not be much less effective. These fibroblasts are unfortunately detected in a wide array of tumors (including breast, ovary, lung, head and neck and melanoma), indicating that these cells need to be targeted by new therapies.
Thus, a patent revealing the identification of a marker that recognizes these fibroblasts plans to help in establishing a diagnosis and improving patient treatment. Furthermore, a clinical trial is currently being developed by F. Mechta-Grigoriou with several clinicians at Institut Curie, including Drs. E. Romano, A. Vincent-Salomon, F.C. Bidart and G. Zalcman, in order to target this population of fibroblasts and improve the effectiveness of immunotherapy.
"Thus, our study has involved an interdisciplinary team first addressing complex issues from cancer patient samples. From this fundamental research, we obtained data that are clinically relevant and directly adapted in clinical practice, for a real benefit for patients. This is what I like the most in this project," continues Dr. Fatima Mechta-Grigoriou.
Illustration of fibroblast heterogeneity observed in tumors (in this case breast cancers). At least five sub-populations of fibroblasts exist (ecm-myCAF, detox-iCAF, IL-iCAF, TGFβ-myCAF, wound-myCAF) and are detected in various proportions in each patient (shown in each column in figure A) using specific markers (expression of each marker in each cluster shown in figure B). We see (in A) that the “red” sub-population (ecm-myCAF) accumulates significantly in some patients. This is one of the newly identified fibroblast subtype that blocks immunotherapy effectiveness and must be targeted. Dr. Mechta-Grigoriou is now trying to do this with Institut Curie clinicians in a new clinical trial.
Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Yann Kieffer, Hocine R Hocine, Geraldine Gentric, Floriane Pelon, Charles Bernard, Brigitte Bourachot, Sonia Lameiras, Luca Albergante, Claire Bonneau, Alice Guyard, Karin Tarte, Andrei Zinovyev, Sylvain Baulande, Gerard Zalcman, Anne Vincent-Salomon and Fatima Mechta-Grigoriou. Cancer Discov. 2020 May 20:CD-19-1384. doi: 10.1158/2159-8290.CD-19-1384. Online ahead of print. PMID: 32434947