Abstract P040: Harness the immune-modulatory activities of Toxoplasma gondii to improve lymphocyte infiltration into brain tumors

Abstract

Abstract While checkpoint inhibitors carry great promises for T-cells-based immunotherapy for brain tumors, the presence of abundant T cells supported by the tumor microenvironment (TME) is a prerequisite for it to be effective. Our lab and others' work using mouse models and patient samples demonstrated that, Shh-subtype medulloblastoma, a well-studied pediatric brain tumor, lacks both T cell infiltration and a supportive TME, posing a critical barrier for immunotherapy. I envision that the protozoans Toxoplasma gondii (T.gondii) as a biological agent could provide a unique solution, because T.gondii can naturally disseminate to the brain and induce significant infiltration and activation of T cells asymptomatically. We hypothesize that T.gondii could attract T cells into brain tumors while at the same time convert the non-supportive TME into one that is conducive for T cells. Using a mouse model for medulloblastoma based on a genetic system called Mosaic Analysis with Double Markers (MADM) that recapitulates the tumorigenic process in human by producing few and precisely labeled mutant cells, I was able to assess the immuno-modulatory potential of T.gondii in the context of an intact immune system and endogenous TME. Our preliminary data revealed three exciting facets about T.gondii's immunotherapeutic potential. Via histological assessment and flow cytometry, we found that at 24 days post infection, abundant T cells are recruited into TME. Correspondingly, we detected significant elevation of IFNg and IFNg-driven genes in the tumors, suggesting Th-1 immunity presence in TME. Lastly, we found that T.gondii challenge is associated with reduced tumor incidence. These results indicates T.gondii holds potent immuno-modulatory capability and potentially anti-tumoral functions. My follow-up studies with dive more deeply into three aspects: 1) determine whether T. gondii can sustainably recruit functional T cells into the tumor mass; 2) determine whether T. gondii can help shape a T cell-supportive TME, especially through activating Th1-immune response in innate immune cells; and 3) identify the underlying mechanisms for T.gondii to exert tumor-suppressing activities. Citation Format: Yen Nguyen, Xiaoyu Zhao, Sarah Ewald, Tajie Harris, Hui Zong. Harness the immune-modulatory activities of Toxoplasma gondii to improve lymphocyte infiltration into brain tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P040.