Promoting Type-1 CD4+ T Cell Immune Responses Against Tumor-Associated Antigen MAGE-A6
One of the main challenges facing tumor immunologists is to develop strategies that would effectively stimulate Type-1 anti-tumor T cell responses, which have been correlated with better clinical outcome and prolonged survival of cancer patients. As CD4+ T cells were shown to play a critical role in mediating these responses, it was of interest to examine novel ways of effectively stimulating and enhancing Type-1 CD4+ T cell responses. For these studies I used MAGE-A6, a tumor associated antigen (TAA) expressed by a broad range of human cancer types. Two novel MAGE-A6 T-helper epitopes were identified and were shown to be recognized by CD4+ T cells isolated from the majority of normal donors or patients with melanoma, regardless of their HLA genotype (i.e. poly-DR presented epitopes). Furthermore, peptide-specific T cells also recognized autologous monocytes pulsed with recombinant MAGE-A6 protein, supporting the natural processing and MHC presentation of these epitopes. Interestingly, one of the novel MAGE-A6 epitopes possesses a high-degree of homology with a microbial peptide. CD4+ T cells stimulated in vitro with this microbial peptide cross-reacted against the MAGE-A6 homologue peptide, and could recognize naturally-processed MAGE-A6 epitopes more effectively than T cells stimulated with MAGE-A6 peptides. This study showed that it is possible to stimulate, and even enhance tumor-specific T cell responses using microbial epitopes that are homologous to TAA-derived peptides. In the final study, human dendritic cells (DC) were engineered to secrete high levels of IFN-×-inducing cytokines IL-12p70 and IL-18 via recombinant adenoviral infection to generate an in vitro stimulus capable of promoting previously deficient patient Th1-type responses. DC engineered to secrete both of these cytokines simultaneously (DC.IL-12/18) were highly effective at stimulating MAGE-A6-specific Th1-type CD4+ T cell responses from patients with melanoma, particularly when loaded with MAGE-A6 protein. Poly-DR presented epitopes and MAGE-A6 protein defined in this thesis, if loaded onto DC.IL-12/18, could prove clinically useful as a vaccine modality capable of promoting the recovery and/or enhancement of tumor antigen-specific, Th1-type CD4+ T cell responses in the majority of patients harboring MAGE-A6+ cancers.
Advisor:William Chambers; Hannah Rabinowich; Louis Falo; Russell Salter; Ora A. Weisz; Walter J. Storkus; Angus Thomson
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Date of Publication:06/29/2006