CD74 supports accumulation and function of regulatory T cells in tumors

• Published in: Nature communications Vol. 15; no. 1; p. 3749
• Main Authors: Bonnin, Elisa, Rodrigo Riestra, Maria, Marziali, Federico, Mena Osuna, Rafael, Denizeau, Jordan, Maurin, Mathieu, Saez, Juan Jose, Jouve, Mabel, Bonté, Pierre-Emmanuel, Richer, Wilfrid, Nevo, Fabien, Lemoine, Sebastien, Girard, Nicolas, Lefevre, Marine, Borcoman, Edith, Vincent-Salomon, Anne, Baulande, Sylvain, Moreau, Helene D., Sedlik, Christine, Hivroz, Claire, Lennon-Duménil, Ana-Maria, Tosello Boari, Jimena, Piaggio, Eliane
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/107; 13/31; 14/19; 14/28; 38/91; 631/250/1619/554/1898/1271; 631/250/24/1529; 631/67/1857; 64/60; 692/4028/67/580; Accumulation; Actin; Animal models; Animals; Anticancer properties; Antigen-presenting cells; Antigens; Antigens, Differentiation, B-Lymphocyte - genetics; Antigens, Differentiation, B-Lymphocyte - immunology; Antigens, Differentiation, B-Lymphocyte - metabolism; Antitumor agents; Biology; Chemical Sciences; Cytology; Cytoskeleton; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - immunology; Histocompatibility Antigens Class II - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Immunoregulation; Invariant chain; Invariants; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Major histocompatibility complex; Mice; Mice, Inbred C57BL; Mice, Knockout; Microenvironments; multidisciplinary; Neoplasms; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Organelles; Phenotypes; Science; Science (multidisciplinary); T-Lymphocytes, Regulatory - immunology; Tumor Microenvironment - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47981-3

Regulatory T cells (Tregs) are plastic cells playing a pivotal role in the maintenance of immune homeostasis. Tregs actively adapt to the microenvironment where they reside; as a consequence, their molecular and functional profiles differ among tissues and pathologies. In tumors, the features acquired by Tregs remains poorly characterized. Here, we observe that human tumor-infiltrating Tregs selectively overexpress CD74, the MHC class II invariant chain. CD74 has been previously described as a regulator of antigen-presenting cell biology, however its function in Tregs remains unknown. CD74 genetic deletion in human primary Tregs reveals that CD74KO Tregs exhibit major defects in the organization of their actin cytoskeleton and intracellular organelles. Additionally, intratumoral CD74KO Tregs show a decreased activation, a drop in Foxp3 expression, a low accumulation in the tumor, and consistently, they are associated with accelerated tumor rejection in preclinical models in female mice. These observations are unique to tumor conditions as, at steady state, CD74KO-Treg phenotype, survival, and suppressive capacity are unaffected in vitro and in vivo. CD74 therefore emerges as a specific regulator of tumor-infiltrating Tregs and as a target to interfere with Treg anti-tumor activity. CD74, the MHC class II invariant chain, was thought to be mainly expressed by antigen presenting cells. Here the authors report that CD74 is overexpressed by human tumor infiltrating regulatory T cells (Tregs) and that its loss affects Treg accumulation and function in tumors.