Correcting T-cell immunosuppression may unleash powerful antitumor responses; however, knowledge about the mechanisms and modifiers that may be targeted to improve
therapy remains incomplete. Here, we report that
polyamine elevation in
cancer, a common metabolic aberration in aggressive lesions, contributes significantly to
tumor immunosuppression and that a
polyamine depletion strategy can exert antitumor effects that may also promote immunity. A
polyamine-blocking
therapy (PBT) that combines the well-characterized
ornithine decarboxylase (ODC) inhibitor
difluoromethylornithine (DFMO) with AMXT 1501, a novel inhibitor of the
polyamine transport system, blocked
tumor growth in immunocompetent mice but not in athymic nude mice lacking T cells. PBT had little effect on the proliferation of epithelial
tumor cells, but it increased the number of apoptotic cells. Analysis of CD45(+)
tumor immune infiltrates revealed that PBT decreased levels of Gr-1(+)CD11b(+) myeloid suppressor cells and increased CD3(+) T cells. Strikingly, in a model of
neoadjuvant therapy, mice administered with PBT one week before surgical resection of engrafted mammary
tumors exhibited resistance to subsequent
tumor rechallenge. Collectively, our results indicate that
therapies targeting
polyamine metabolism do not act exclusively as antiproliferative agents, but also act strongly to prevent immune escape by the
tumor. PBT may offer a general approach to heighten immune responses in
cancer.