CD68 is a lysosome-associated membrane protein mainly expressed in the mononuclear-macrophage system and belongs to the scavenger receptor family. This protein participates in the transport and phagocytosis processes of the intracellular membrane through its unique LAMP-like domain and plays an important role in antigen presentation and inflammatory responses. As a specific marker of macrophages, CD68 exhibits a characteristic high expression pattern on tumor-associated macrophages in the tumor microenvironment, making it an important target for tumor immunology research. Since its identification in 1991, the discovery of CD68 has provided an important tool for studying macrophage heterogeneity and its role in diseases, and has significant application value in the fields of immunohistochemical diagnosis and immunotherapy.
CD68 is a lysosome-associated membrane glycoprotein with a molecular weight of approximately 110kDa, and its molecular weight varies among different species. The following is a comparison of the molecular characteristics of CD68 in common species:
| Species | Human | Mice | Rats | Pigs | Bovine |
| Molecular Weight (kDa) | 110 | 105 | 108 | 112 | 109 |
| Primary Structural Differences | Contains LAMP-like domains | Slightly less glycosylation sites | Transmembrane region conserved | Modify different sugar chains | High homology with human |
The CD68 protein is composed of approximately 300 amino acids, and its primary structure contains a characteristic lysosome-associated membrane protein (LAMP) domain. This protein has a typical type II transmembrane structure, including a short N-terminal cytoplasmic tail region, a single transmembrane region, and a large C-terminal intracavitary domain. The intracavitary region of CD68 contains multiple glycosylation sites, which endows it with high specificity in immunohistochemical detection. This protein mediates its stable expression on the lysosomal membrane of macrophages through its lysosomal localization sequence (LYS), a characteristic that makes it a specific marker of macrophages.
Fig. 1 Schematic representations of the CD68 gene1
Key structural properties of CD68:
The main function of CD68 is to serve as a marker of macrophages and a lysosomal membrane protein, while also participating in multiple immune regulatory processes. The following are the main functions of CD68 and their descriptions:
| Function | Description |
| Macrophage markers | Specific expression in macrophages surface, which is the gold standard by macrophages. |
| Antigen presentation | Participate in MHC class II molecules mediated process of antigen presenting connection inherent immunity and adaptive immunity. |
| Inflammatory regulation | Expression in the inflammatory response, involved in the secretion of proinflammatory factor and inflammatory microenvironment. |
| Phagocytosis | As a scavenger receptor, it recognizes and endocytoses modified LDL, bacteria and other foreign substances. |
| Regulation of the tumor microenvironment | Highly expressed in tumor-associated macrophages, it affects tumor immune escape and angiogenesis. |
The expression level of CD68 is closely related to the activation status of macrophages. Its upregulation usually indicates the activation of M2-type macrophages and plays an important role in chronic inflammation, atherosclerosis and tumor development. Unlike common membrane proteins, CD68 is mainly located on the lysosomal membrane. This characteristic makes it a specific marker for studying the lysosomal function of macrophages.
1. Harris, Jonathan A., et al. "CD163 versus CD68 in tumor associated macrophages of classical Hodgkin lymphoma." Diagnostic pathology 7 (2012): 1-6.https://doi.org/10.1186/1746-1596-7-12
This study compared the expression of CD68 and CD163 in classical Hodgkin's lymphoma and found that CD68 was more expressed in tumor nodules but had stronger background staining, while CD163 had better specificity and was a superior tumor-associated macrophage marker. However, neither of them was significantly correlated with the recurrence of the disease.
2. Zhang, Jingwei, et al. "Role of CD68 in tumor immunity and prognosis prediction in pan-cancer." Scientific reports 12.1 (2022): 7844. https://doi.org/10.1038/s41598-022-11503-2
Research has found that CD68 is highly expressed in various tumors and is associated with poor prognoses such as glioblastoma and clear cell renal cell carcinoma, but it has a better prognosis in chromophobe renal cell carcinoma. High expression of CD68 affects immune infiltration and drug response, and may become a new target for immunotherapy.
3. Pelekanou, Vasiliki, et al. "CD68, CD163, and matrix metalloproteinase 9 (MMP-9) co-localization in breast tumor microenvironment predicts survival differently in ER-positive and-negative cancers." Breast Cancer Research 20 (2018): 1-10. https://doi.org/10.1186/s13058-018-1076-x
Research has found that high expression of CD68 is associated with a poorer prognosis in ER-negative breast cancer patients, while high expression of CD163 indicates improved survival in ER-negative patients. TAMs of CD68+/CD163+/MMP-9+ are significantly associated with poor prognosis in ER-positive breast cancer and may become a new direction for targeted therapy.
4. Möller, Alexander, et al. "The roles of toll-like receptor 4, CD33, CD68, CD69, or CD147/EMMPRIN for monocyte activation by the DAMP S100A8/S100A9." Frontiers in Immunology 14 (2023): 1110185. https://doi.org/10.3389/fimmu.2023.1110185
Research has found that in the monocyte inflammatory response induced by S100A8/A9, TLR4 is a key receptor, while the knockout of surface receptors such as CD68 does not affect cytokine release. CD68 is not the main target of the inflammatory response mediated by the S100 protein.
5. Song, Li, Carolyn Lee, and Christian Schindler. "Deletion of the murine scavenger receptor CD68 [S]." Journal of lipid research 52.8 (2011): 1542-1550. https://doi.org/10.1194/jlr.M015412
The article indicates that CD68, as a member of the scavenger receptor family, knockout experiments show that it is not a key mediator for the uptake of oxidized low-density lipoprotein, but it may negatively regulate the function of antigen-presenting cells and affect the MHC-II molecule presentation pathway.
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