ONGOING RESEARCH INITIATIVES:
Leveraging CD4 T cell help for in situ cancer vaccination. We discovered that treating tumors with childhood vaccines, in particular polio and tetanus, mediates antitumor efficacy by coordinating antitumor CD8 T cells and eosinophils by re-activating (i.e., ‘recall’ of) vaccine-specific memory CD4 T cells (Brown et al JITC 2023). These studies reveal potential for childhood vaccines to accomplish in situ vaccination by enlisting local CD4 T cell help, and implies that Th2 polarized CD4 T cells and type II immune responses can positively influence cancer immune surveillance. Ongoing research is focused on optimizing ‘recall’ antigen density and character to maximize antitumor effects of CD4 T cell recall, resolving the role of eosinophils and type II immune mediators in cancer immune surveillance, as well as developing novel therapeutic strategies—including combining with PRR-engaging therapies— based upon these concepts.
Defining and optimizing antitumor T cell engagement after virotherapy and in situ vaccination. We discovered that type I IFNs are necessary, but not sufficient alone, to induce productive antitumor T cell activity in the context of in situ vaccination and virotherapy (Brown et al Nat Comm 2021). Our current work is resolving cellular, chemokine and cytokine determinants of successful in situ vaccination; as well as optimizing new PRR-engaging strategies that provoke Type I IFN contextualized innate inflammation commensurate with productive antitumor T cell engagement. Amongst these approaches include new delivery routes and strategies for polio virotherapy in collaboration with the Gromeier Lab, exploring the utility of peripheral and antitumor ‘priming’ of innate immunity prior to in situ vaccination, developing novel virotherapy candidates with broader type I IFN contextualized inflammatory footprints, as well as mechanistically explaining correlates of successful in situ vaccination in glioma patients.
Resolving targetable sex differences in brain tumor immune surveillance. In collaboration with Donald McDonnell’s research group, we are testing the role of sex hormones in influencing intratumor innate immunity, in particular in tumor associated myeloid cells, as a route to revive glioma immune surveillance. The goals of this project are to define sex differences and respective roles for sex hormone signaling in brain tumor immune surveillance, determine the role of sex hormone signaling in dictating glioma immune resistance, and to test if clinically available sex hormone modulators can be repurposed to target brain tumors.
Ex vivo glioma slice cultures as a pre-clinical model of anti-glioma drug discovery. Leveraging the strength of the Preston Robert Tisch Brain Tumor Biorepository, our team developed an ex vivo slice culture glioma model that differs from commonly used organoid and cell line techniques in that the native tumor microenvironment and architecture remains intact. We are using this model to define therapy potential of diverse in situ vaccine modalities, virotherapies, novel chemotherapy strategies, and combinations thereof to demonstrate mechanisms of action in human glioma tissue, identify biomarkers and mechanisms of resistance to therapy, and nominate new therapy strategies for gliomas.
