Background The aspiration of cancer immunotherapy is to generate large numbers of highly functional anti-tumor CD8+ T-cells. We and others have optimized Listeria monocytogenes as a powerful anti-cancer vaccine platform to drive such T-cell responses. Early clinical trial data suggest the number of T-cells generated correlates with efficacy, demanding an understanding of the factors that dictate vaccine-induced T-cell responses. The CD8+ T-cell response is intimately linked to magnitude and quality of the innate immune response triggered by vaccines. Listeria-based vaccines activate numerous innate pathways and can be engineered to hyper- or hypo-induce these pathways. We sought to understand how modulating innate immunity would impact vaccine efficacy.
Methods To dissect the impact of type I interferon signaling and the inflammasomes on L. monocytogenes induced T-cell responses, we immunized IFNAR-/-, Caspase1/11-/-, and novel IFNAR-/-Caspase1/11-/- double knockouts mice we generated for this study. CD8+ T-cell responses were assessed at the peak T-cell response, after contraction and memory formation, and after rechallenge. The phenotype and magnitude of CD8+ T-cells was assessed at each stage, and functional outcomes were assessed by measuring protection from reinfection by wild-type Listeria.
Results IFNAR-/- mice developed the largest number of CD8+ T-cells during the peak primary response contradicting the dogma that Type-I Interferon promotes robust CD8+ T-cell responses. Caspase1/11-/- mice were not significantly different from wild-type mice. The frequency of short-lived effector cells (assessed by expression of CD127 and KLRG1) was no different between wild-type and IFNAR-/- mice, however we observed more than twice as many memory precursor cells at the peak CD8+ T-cell response. These findings extend to the memory and recall stage with more antigen-specific T-cells observed after contraction and upon rechallenge. Finally, IFNAR-/- mice are remarkably more protected from wild-type Listeria rechallenge than their counterparts after immunization demonstrating the efficacy of the increased memory T-cell pool. Data are representative of at least two independent replicates with at least 5 mice per group and significance was assessed by one-way ANOVA with *p<0.05.
Conclusions We demonstrated that type-I interferon signaling deficiency leads to enhanced prophylactic vaccine efficacy through increased memory T-cell formation. Ultimately, for patients with slow growing tumors or with high-risk mutations, prophylactic tumor vaccines could elicit life-long protection from disease. Importantly, increased memory precursor T-cell abundance did not come at the expense of short-lived effectors leaving open the possibility that blocking Type-I IFN could potentiate lasting immunological memory in both the therapeutic and prophylactic setting.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.