Unique Phenotypic and Functional Properties of a Cancer Vaccine Based on Attenuated Listeria Monocytogenes

Listeria;Cancer Vaccine;Checkpoint Proteins;PD-1;LAG-3;CD8α+ DC;Immunology

Nirschl, Christopher JamesDrake, Charles G ;

Johns Hopkins University

关键词: Listeria;    Cancer Vaccine;    Checkpoint Proteins;    PD-1;    LAG-3;    CD8α+ DC;    Immunology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60240/NIRSCHL-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Live, attenuated vaccinations have been successful in the generation of protective immunity to a variety of illnesses, such as the measles, mumps, and rubella, but have had limited success as therapeutic cancer treatments. We explored the differences in the cellular and molecular immunity generated by a new Listeria Monocytogenes vaccine platform, as compared to the well characterized Vaccinia Virus. Listeria-OVA vaccination resulted in the slowest tumor growth in subcutaneous models, as well as decreased tumor burden and increased survival in a metastatic model. This benefit was dependent on the generation of adaptive immunity, as antibody depletion of CD8+ T cells significantly impaired the survival benefit of the Listeria-OVA vaccine. To examine the effects of these vaccines on the early stages of CD8+ T cell development, we adoptively transferred OVA specific CD8+ T cells (OT-1) into host mice prior to vaccination. Surprisingly, we found that Listeria-OVA vaccine resulted in CD8+ T cell activation without significant expression of PD-1 or LAG-3, unlike the Vaccinia-OVA vaccine or any other vaccine currently reported. The activation of CD8+ T cells without PD-1 was completely dependent on the genetic deletion of the ActA gene from the Listeria vector, as wildtype Listeria-OVA did not replicate this phenotype. Strikingly, despite differences in wildtype mice, both vaccines were similarly effective in increasing overall survival in PD-1-/- mice, suggesting that the difference in induced PD-1 expression was responsible for the difference in efficacy. To better understand this phenotype, we developed a direct ex vivo antigen detection assay, and found that both Vaccinia-OVA and Listeria-OVA are primarily presented to naïve CD8+ T cells by CD8α+ dendritic cells (CD8α+ DC), and that Listeria-OVA vaccinated CD8α+ DCs are sufficient to drive naïve CD8+ T celldivision without PD-1 expression in a contact dependent manner. Finally, we performed microarray analysis on CD8α+ DCs 24 hours after vaccination, and found a dramatic difference in the RNA expression profile of a Listeria-OVA vaccinated CD8α+ DCs. Together, these data show that checkpoint protein expression is not uniformly associated with CD8+ T cell activation, and that individual cancer vaccine vectors may increased clinical benefit due to their modulation of checkpoint protein expression.