Temporally Programmed CD8α+ DC Activation Enhances Combination Cancer Immunotherapy
Alice Tzeng1*, Monique J. Kauke1, Eric F. Zhu1, Kelly D. Moynihan1, Cary F. Opel1, Nicole J. Yang1, Naveen Mehta1, Ryan L. Kelly1, Gregory L. Szeto2, Willem W. Overwijk3, Darrell J. Irvine1, K. Dane Wittrup1
1Massachusetts Institute of Technology, Cambridge MA 02139, 2University of Maryland Baltimore County, Baltimore MD 21250, 3The University of Texas M.D. Anderson Cancer Center, Houston TX 77030
Much attention has focused on determining which immunotherapeutic drug classes exhibit synergistic antitumor activity, while comparatively little effort has been directed towards evaluating the importance of dose schedules for these combinations. Using established syngeneic tumor models, we found that the relative timing of drug administration can play a pivotal role in dictating combination immunotherapy outcomes. Specifically, staggering IFNα administration after, rather than before or simultaneously with, serum-persistent IL-2 and tumor-specific antibody significantly increased long-term survival and generated immunological memory. Successful combination therapy required IFNα-induced activation of cross-presenting CD8α+ DCs following release of antigenic tumor debris by the IL-2-and-antibody-mediated immune response. Due to decreased phagocytic ability post-maturation, DCs activated too early captured much less antigen and could not effectively prime CD8+ T cells. Thus, a two-day delay in DC-activating IFNα administration following the injection of tumoricidal therapy yielded a ~85% survival rate, in stark contrast to 0% long-term survivors when both therapies were given simultaneously. We provide further generalization, with multiple combination therapies that activate DCs through distinct pathways, that superior tumor control is achieved by temporally programming DC activation to occur after the culmination of tumor-killing activity. This work presents a simple strategy for augmenting efficacy in the combinatorial treatment setting and highlights dose schedule as an underappreciated factor that can profoundly affect the success of multi-component immunotherapies.