Overcoming T Cell Tolerance Against Endogenous Choroid Plexus Tumors Using a Combination Immunotherapy

We target T cells escaping clonal deletion to study effects of a combination of immunotherapies against endogenously arising choroid plexus tumors. The model we use is the SV11 mouse transgenic for large T antigen of simian virus 40. Mice are immunologically tolerant to the choroid plexus tumor. We found that systemic administration of the proinflammatory TH1 cytokine, IL-12, increased survival and tumor T cell infiltrate. The addition of costimulation through an anti-CD28/Folate bispecific conjugate, PV-1 Fab/Folate, further enhanced survival and dramatically slowed tumor growth. Furthermore, proliferating CD8 T cells were found in tumors of treated animals. However, upon treatment withdrawal, tumors rapidly progressed and all animals eventually succumbed to the tumor. To supplement T cell activation, we investigated the possible recruitment of microglia, hoping to increase endogenous antigen presentation. Microglia phagocytosed apoptotic tumor cells and present class I MHC peptide antigen, inducing proliferation of naive CTLs in vitro. Furthermore, microglia enhanced proliferation of naive peptide specific CTLs incubated with primary splenocytes and high affinity peptide. We postulate that supplementing the immune response created with IL-12 and PV-1 Fab/Folate by increasing antigen presentation, peripherally activated T cells infiltrating the tumor parenchyma will receive the required stimulation for efficient activation. Immunotherapy with naive low-affinity, anti-tumor CTLs will most likely involve combinations of strategies stimulating the signaling pathways needed to activate and sustain a specific T cell response strong enough to overcome tumor growth, CNS immunosuppression, and self-tolerance.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Neuroscience

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Gawlick, Ute

Contributors dc:contributor

• Roy, Edward J.

• Biology, Neuroscience

Language dc:language

eng

Identifier

(MiAaPQ)AAI3182268

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/82501