Cd74, also known as MHC class II invariant chain (Ii), is a non-polymorphic type II transmembrane glycoprotein. It serves as a chaperone for MHC class II molecules, participating in antigen presentation. Additionally, Cd74 is a cell-membrane high-affinity receptor for macrophage migration inhibitory factor (MIF), D-dopachrome tautomerase (D-DT/MIF-2) and bacterial proteins. Activation of the Cd74/CD44 receptor complex can lead to multiple intracellular signal pathways such as ERK1/2, PI3K-Akt, NFκB, and AMPK pathways, playing crucial roles in immune-related biological processes [1].

Genetic deletion of Cd74 in human primary Tregs shows that Cd74KO Tregs have major defects in actin cytoskeleton and intracellular organelle organization. Intratumoral Cd74KO Tregs display decreased activation, reduced Foxp3 expression, and low tumor accumulation, associated with accelerated tumor rejection in female mice, indicating Cd74 is a specific regulator of tumor-infiltrating Tregs [2]. In cervical cancer, blocking tumor-associated macrophage-derived Cd74 enhanced macrophage phagocytosis, decreasing cancer cell viability in vitro and in vivo, suggesting targeting Cd74 can augment neoadjuvant therapeutic efficacy [3].

In summary, Cd74 is essential for protein trafficking, immune cell regulation, and signal transduction. Studies using Cd74 KO models have revealed its role in tumor-infiltrating Tregs and in enhancing anti-tumor efficacy in cervical cancer, highlighting its potential as a therapeutic target in cancer immunotherapy.

References:

1. Su, Huiting, Na, Ning, Zhang, Xiaodong, Zhao, Yong. 2016. The biological function and significance of CD74 in immune diseases. In Inflammation research : official journal of the European Histamine Research Society ... [et al.], 66, 209-216. doi:10.1007/s00011-016-0995-1. https://pubmed.ncbi.nlm.nih.gov/27752708/

2. Bonnin, Elisa, Rodrigo Riestra, Maria, Marziali, Federico, Tosello Boari, Jimena, Piaggio, Eliane. 2024. CD74 supports accumulation and function of regulatory T cells in tumors. In Nature communications, 15, 3749. doi:10.1038/s41467-024-47981-3. https://pubmed.ncbi.nlm.nih.gov/38702311/

3. Wang, Zixiang, Wang, Bingyu, Feng, Yuan, Zhang, Youzhong, Cui, Baoxia. 2024. Targeting tumor-associated macrophage-derived CD74 improves efficacy of neoadjuvant chemotherapy in combination with PD-1 blockade for cervical cancer. In Journal for immunotherapy of cancer, 12, . doi:10.1136/jitc-2024-009024. https://pubmed.ncbi.nlm.nih.gov/39107132/