Trends in Immunology
CD1a in human cancers: a new role for an old molecule
Section snippets
CD1a molecular structure
CD1a belongs to the highly conserved and closely related group of CD1 proteins, with CD1a, CD1b and CD1c belonging to group 1 CD1 molecules and CD1d belonging to group 2, based on sequence similarity. CD1e, a non-membrane form has also recently been described. In murine systems, only group 2 CD1d molecules are found and much of the work on CD1 structure and function has therefore been done using CD1d in mouse models (reviewed in Ref. [1]). All CD1 molecules, except CD1e, are cell surface
CD1 function and induction
T cells have long been demonstrated to react with MHC-presented peptide antigens and interest in glycolipid antigens has focused primarily on antibody responses. All membrane-bound isoforms of the CD1 family present hydrophobic ligands, such as lipid and glycolipid antigens, and the CD1 pathway is well recognized in the immunological defense against certain bacteria with lipid-rich capsular surface antigen molecules (reviewed in Ref. [5]). CD1d-restricted T cells are natural killer T (NKT)
CD1a tissue expression
CD1a was first described as a molecule on thymocytes and certain thymomas. Group 1 CD1 molecules are expressed on double-positive (CD4+CD8+) cortical thymocytes and with less intensity on CD4 or CD8 single-positive thymocytes (reviewed in Ref. [2]). CD1a, b and c are expressed on dermal dendritic cells and Langerhans cells (reviewed in Refs 2, 10). Strictly, monocytes do not express group 1 CD1 molecules, although these molecules are induced by treatment with granulocyte–macrophage colony
Expression and regulation of CD1a on DCs
Several factors modify the expression of CD1a and other molecules on DCs in vitro and in vivo. In vivo, three different fractions of DC from normal human blood can be isolated [15]: CD1a+CD11c+ (double-positive) CD1a−CD11c− (double-negative) and CD1a−CD11c+ (single-positive) populations. The CD1a+CD11c+ population is the most direct precursor of Langerhans cells and can be differentiated into Langerhans cells in vitro with GM-CSF, IL-4 and transforming growth factor-β (TGF-β). As discussed in
CD1a density, DC activation and survival in human malignancies
DC density, using predominantly CD1a or S100, has been documented in human gastric, thyroid, lung, colorectal, renal, prostate, bladder, breast, laryngeal, oesophageal, nasopharyngeal and oral cancers (reviewed in Refs 26, 27). DC density or activation has been positively associated with improved clinical outcome (Table 2). S100 stains formalin-fixed archival tissues and was one of the first markers used to identify DCs, therefore, more data are currently available using S100 as a DC marker
Possible role of CD1a in human malignancies
The precise role of CD1a on the surface of DCs in the recognition of transformed malignant cells is not defined. Tumour cells are known to undergo changes in their ganglioside expression profile compared with non-malignant cells. The activation of the cellular arm of the immune response in patients vaccinated with GM3, an ubiquitous ganglioside antigen overexpressed in several epithelial tumour types, or N-Glycolyl-GM3 (a molecule not expressed in normal tissues and recently found in several
Effects of gangliosides
Tumour-derived gangliosides inhibit the tumour-specific immune response 51, 52, impede maturation of MoDCs [53], inhibit DC differentiation from monocytes 54, 55, 56 and induce apoptosis in MoDCs [55] and T cells [57]. Expression of CD1a on MoDCs is reduced by gangliosides 55, 56. Overexpression of gangliosides does not appear to affect tumour cells, perhaps because gangliosides are often shed into the microenvironment, however, tumour growth could be reduced by inhibition of ganglioside
Concluding remarks
The intriguing relationship between DC density, activation and survival in human cancers requires further investigation to define the underlying mechanisms. Some patients show long dormant periods between surgical resection of tumours and tumour recurrence indicating some control of malignant cell growth. Several possible mechanisms within the tumour microenvironment are capable of successfully limiting tumour growth in vivo. These include angiogenesis, apoptosis, cell cycle control and
Acknowledgments
Earlier work leading to some of the findings concerning CD1a cells in tumours was supported by the Cancer Council (formerly Anti-Cancer Foundation) of South Australia, Royal Australasian College of Surgeons (Hooper and Florance Fellowships), and the National Health and Medical Research Foundation of Australia. We wish to thank Heddy Zola (Adelaide) and Gus Nossal (Melbourne) for reviewing the manuscript.
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