A Quantum Leap Thanks to Work from the Falcone Laboratory
Major work carried out by the laboratory of Dr. Emilia Liana Falcone, researcher and Director of the Microbiome and Mucosal Defense Research Unit at the Montreal Clinical Research Institute (IRCM), in collaboration with Dr. Uzel (NIH) and Dr. Grimbacher (University of Freiburg), and recently published in the scientific journal Microbiome, describe for the first time the intestinal microbiome and metabolome in patients with (genetically acquired) CTLA4 deficiency.
CTLA4 is an immune checkpoint, a key element in cancer mechanisms, which has revolutionized the field since it was discovered. With this study, entitled “The intestinal microbiome and metabolome discern disease severity in cytotoxic T-lymphocyte-associated protein 4 deficiency”, further interactions between immune responses and the microbiome have been uncovered.
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In 2018, Dr. James Allison and Professor Tasuku Honjo were awarded the Nobel Prize in Physiology or Medicine for their discovery of cancer treatment by inhibiting negative immune regulation. |
In this study, two cohorts of patients with genetically acquired CTLA4 deficiency were evaluated, from two different continents. Interestingly, these patients show clinical similarities with patients having side effects associated with treatment with immune checkpoint inhibitors used to treat certain cancers.
Observations
Two bacterial genera emerged as biomarkers to distinguish patients with inherited CTLA4 deficiency from healthy individuals, from both the National Institutes of Health (NIH) in the USA and a geographically distinct cohort from the Center for Chronic Immunodeficiency (CCI) at the Medical Center - University of Freiburg in Germany. Since inborn errors of immunity in general can be associated with disturbances of the microbiota, a disease-control cohort of individuals with common variable immunodeficiency (CVID) was also included in the study. Despite common changes in the microbiome associated with inborn errors of immunity, both bacterial genera retained their specificity as biomarkers of CTLA4 deficiency. The researchers also identified gut microbiome and metabolome signatures that distinguished CTLA4-deficient patients with severe disease from those with mild disease.
Changes in the microbiome were associated with distinct metabolomic profiles. These differences were influenced by the presence of gastrointestinal manifestations and were partially reversed by treatment with certain immune modulators.
Conclusions
Disturbances in the gut microbiome leading to metabolomic changes have been observed in patients with hereditary CTLA4 deficiency. Although some of these features were associated with another inborn error of immunity, the distinct changes associated with CTLA4 deficiency underline the fact that microbiome changes associated with inborn errors of immunity probably reflect underlying immune dysregulation. Identified gut microbial and metabolic biomarkers that distinguish CTLA4-deficient individuals according to disease severity should be further prospectively studied to determine their predictive value and investigated as potential therapeutic targets.
Acknowledgements
This project was supported by the Division of Intramural Research (DIR), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genomic Research Institute (NHGRI) and the Bioinformatics and Computational Biosciences Branch (BCBB) Service Contract HHSN3162013000006W of the National Institutes of Health (NIH). This study was funded in part by NIH Bench-to-Bedside (BtB) Program grant480707 “Deciphering Immune Dysregulation Due to Germline CTLA4 Mutations”. B. G. is funded by the Deutsche Forschungsgemeinschaft (RESIST - EXC 2155 - Project ID 390874280 ; CIBSS - EXC-2189 - Project ID 390939984 ; SFB1160/3_B5 ; and GR 1617/17-1 - project no. 519635399), the EU-funded IMMERGE PhD program (https:// immergeproject.eu), the BMBF rare diseases program (GAIN 01GM2206A), and the Wilhelm Sander-Stiftung, Förderantrags-Number. 2023.115.1.
Dr. Falcone's work has been supported by a Canada Research Chair (Tier 2) on “The Role of the Microbiome in Innate Errors of Immunity and Post-Infectious Conditions”, the Canadian Institutes of Health Research (CIHR), the Fonds de recherche du Québec (FRQ) and a Fondation J-Louis Lévesque Research Chair.
About Dr. Falcone
Dr. Emilia Liana Falcone is a leading expert in the study of host-microbiome interactions, and long COVID. She holds the Canada Research Chair (Tier 2) on the role of the microbiota in inborn errors of immunity and post-infectious conditions, and is a Clinical Assistant Professor in the Faculty of Medicine - Department of Medicine and Department of Microbiology, Infectious Diseases and Immunology at the Université de Montréal. She is also the Director of the Microbiome and Mucosal Defense Research Unit at the IRCM and the Director of the IRCM post-COVID-19 research clinic. She is the recipient of several prestigious awards recognizing her excellence in her fields of research.
