The Efficacy of an IL-1α Vaccine Depends on IL-1RI Availability and Concomitant Myeloid-derived Suppressor Cell Reduction

We recently reported that tumor-derived interleukin (IL)-1beta strongly promotes tumor growth by inducing myeloid-derived suppressor cell (MDSC) and regulatory T-cell (T(reg)) expansion. To see whether redirection of an immune response can be achieved through immune response-supporting IL-1alpha application, IL-1RI competent (IL-1RI(comp)) and IL-1RI-deficient (IL-1RI(-/-)) mice received IL-1alpha cDNA-transformed attenuated Salmonella typhimurium (SL-IL-1alpha) and/or lysates from methycholanthrene-induced IL-1(comp) or IL-1(-/-) fibrosarcoma cells. Vaccination with SL-IL-1alpha and/or tumor lysate exerted only a minor effect on the survival of IL-1alpha/beta(-/-) and none on IL-1alpha(comp) tumor-bearing mice despite induction of a potent antitumor response, that was overridden by intratumoral and systemic expansion of MDSC. Application of all-trans-retinoic acid together with anti-CD25 efficiently coped with MDSC and T(reg) expansion. Vaccination concomitantly with application of all-trans-retinoic acid and anti-CD25 treatment significantly increased the survival time and rate of IL-1alpha/beta(comp), but even of IL-1alpha(-/-)beta(comp) IL-1RI(comp) tumor-bearing mice. Instead, in IL-1RI(-/-) mice, though MDSC expansion was weaker, SL-IL-1alpha application hardly displayed any therapeutic efficacy, which implies signal transduction through IL-1alpha binding to the IL-1RI as an essential component for immune response induction. Taken together, IL-1alpha can efficiently support tumor vaccination, as far as expansion of MDSC and T(reg) is controlled. However, care should be taken to interfere with MDSC expansion/activation not through a blockade of the IL-1RI, which is the preferential target of IL-1alpha.