The efficacy of an IL-1alpha 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.
Weiss
Tobias
T
Department of Tumor Cell Biology, University Hospital of Surgery and German Cancer Research Center, Heidelberg, Germany.
Vitacolonna
Mario
M
Zöller
Margot
M
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D005354:Fibrosarcoma / Q000139:chemically induced / Q000628:therapy*; D016233:Immunotherapy, Active; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016896:Treatment Outcome; D014212:Tretinoin / Q000276:immunology / Q000378:metabolism
D019496:Cancer Vaccines; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D053573:Receptors, Interleukin-1 Type I; D014212:Tretinoin