The endoplasmic reticulum
aminopeptidase associated with Ag processing, ERAAP, plays an important role in the trimming of antigenic
peptides for presentation at the cell surface complexed with
MHC class I molecules.
Tumors express varying levels of ERAAP, highlighting a possible mechanism of immune-evasion through alteration of the
peptide repertoire. Using the CT26
tumor model, we investigated the effects of ERAAP modulation on
peptide presentation and the use of ERAAP inhibition as an antitumor
therapy. We show that generation of the cross-protective
tumor Ag GSW11 in the
colorectal carcinoma CT26 is increased when ERAAP expression is reduced. BALB/c mice with reduced ERAAP expression challenged with CT26 induced protective immunity that was mediated by CD8(+) T cells. This antitumor immunity also protected mice when rechallenged with wild-type CT26
tumor; strong CD8(+) T cell responses to GSW11 were observed, despite its presentation being considerably lower. Furthermore, boosting the
tumor immunogenicity through inhibition of ERAAP function with the small molecule inhibitor
leucinethiol in vitro, or in established
tumors in vivo, abrogated
tumor growth and prolonged survival. Thus, our results highlight the promising possibility of using modulation of ERAAP to generate protective antitumor responses as a strategy for
cancer immunotherapy.