Tumor antigen processing and presentation on MHC Class II molecules for CD4⁺ T cell recognition in health and disease

Marturano, Jill (2007). Tumor antigen processing and presentation on MHC Class II molecules for CD4⁺ T cell recognition in health and disease. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000fa54

Abstract

Animal models have shown that CD4⁺ T cells are required to achieve effective, long-lasting immunity to cancer. Less is known on the role and functional state in human disease of tumor antigen specific CD4⁺ T cells. These cells recognise epitopes from tumor antigens presented by MHC-II molecules on professional antigen presenting cells and also directly on tumor cells. MAGE-3 is a tumor specific antigen expressed in tumors of different histology but not healthy tissues and so is an ideal candidate for immunotherapeutic purposes. MAGE-3 CD4 naturally processed epitopes have been described.

The aims of the project were to analyse how processing influences the repertoire of MAGE-3 CD4 epitopes formed in different antigen expressing cell types and the role of MAGE-3 epitope specific CD4⁺ T cells in the natural response of advanced melanoma patients.

Formation of epitopes through the exogenous pathway was differently influenced by endosomal proteases. Indeed, depending on the epitope studied cysteine and aspartic proteases lead to epitope formation or destruction affecting the repertoire presented in vivo. No clear data were obtained to understand the processing pathways in tumor cells, as formation of the studied epitope was unaffected by cytosolic proteases and did not require autophagy.

Most patients had circulating MAGE-3 specific CD4⁺ T cells, mainly unpolarized or producing anti-inflammatory cytokines suggesting an impairment of the anti-MAGE-3 CD4⁺ T cell response in advanced stages of disease. The repertoire of epitopes recognised confirmed the immunodominance of previously described epitopes and correlated well with the results of in vitro processing studies.

Collectively, these experiments show that anti-MAGE-3 CD4⁺ T cell responses develop in vivo and that the repertoire of epitopes formed and recognised is influenced by endosomal proteases. Further studies are needed to investigate factors determining impairment of CD4⁺ T cell function in advanced stages and ways to overcome this dysfunction.