Tumors express many immunogenic antigens, but in most cases the spontaneous response to these antigens by host T cells is poor. This represents a major problem for both immunotherapy and immunogenic chemotherapy. We now describe a population of highly immunogenic dendritic cells (DCs), arising in tumors during immunotherapy, which share attributes of ?conventional? CD103+ cDCs, but which also express lineage-markers of monocytic MDSCs. The scientific premise of the proposal is that this population of ?dual- phenotype? Ly6c+/CD103+ DCs is critical to anti-tumor immune responses during immunotherapy, and that it is possible to therapeutically amplify and increase these cells so as to markedly enhance the effect of immunotherapy.
Aim 1 will test the hypothesis that the Ly6c+/CD103+ DCs arise via rapid differentiation of immature myeloid cells (monocytic MDSCs) in the tumor milieu, via a pathway that requires re-activation of classical DC-lineage transcription factors. The signal that initially drives this differentiation step is inflammation from dying tumor cells, but this is then rapidly amplified by inflammatory signals from activated T cells (positive feedback loop). The hypothesis predicts that Ly6c+/CD103+ DCs are critical for anti-tumor immune responses because they are the only cells in the tumor capable of re-activating anergic/exhausted T cells.
Aim 2 will test the hypothesis that the key mechanism controlling differentiation of Ly6c+/CD103+ DCs is the transcription factor p53 expressed in MDSCs. The hypothesis predicts that p53 acts by inducing expression of the pro- inflammatory transcription factor IRF5; and that the upstream signal for p53 activation is the cell-intrinsic respiratory burst (reactive oxygen species) produced in response to inflammatory cytokines.
Aim 3 will test the translationally-relevant hypothesis that pharmacologic activation of the p53 pathway, using clinically-applicable p53-agonist drugs, will drive the differentiation of increased numbers of Ly6c+/CD103+ DCs during immunotherapy, thus markedly enhancing and prolonging the anti-tumor immune response. To support translation of this approach to humans, this aim will also test the prediction that human myeloid DCs are controlled by an analogous p53-driven, IRF5-dependent maturation pathway. The translational importance of these findings is that they identify myeloid-lineage p53 as a previously unsuspected target for immunotherapy, which can be targeted by existing p53-agonist drugs already under clinical development for other indications.
Strategies to use the body?s own immune system to attack tumors have become very important and timely in the treatment of cancer. However, it is still a major problem that the immunologic milieu inside the tumor is dominantly suppressive and inhibitory. The current proposal builds on novel discoveries to identify drug combinations and pathways that can fundamentally transform the tumor milieu from immunosuppressive to immune activating.