Conventional dendritic cells
Conventional dendritic cells (DCs) infiltrate solid tumors, acquire tumor antigens and migrate to draining lymph nodes. Upon encountering nodal cancer antigen presenting DCs, naïve T cells proliferate and become activated effector cells that egress from lymph nodes and enter tumors. DC tumor exclusion or subversion to dysfunctional states is emerging as a major cause and consequence of tumor growth. In-depth comprehension of DC regulation in the crucial steps of tumor infiltration, antigen capture, migration and T cell priming in draining lymph nodes is needed. The plasticity and heterogeneity of DC subsets demand that integrated multi-dimensional approaches to interrogate DC diversity across homeostatic, tumor, and nodal states are taken. We address these needs by cell transfer and tracing studies, integrated with single cell transcriptomics and functional genomics.
T cell survival and maintenance within the tumor microenvironment depends on in situ cancer antigen presentation, but the cells and pathways involved are poorly understood. We found that a subset of cancer-associated fibroblasts is induced to present MHCII antigens and prime intratumoral CD4+ T cells in human and murine lung carcinomas. Fibroblast-specific targeted ablation of MHCII decreases tumor-infiltrating CD4+ T cell numbers and transcriptional activity, accompanied by an increase in tumor burden. Our findings raise two critical questions: i) which are the regulatory networks that govern antigen-presenting fibroblast differentiation and ii) which co-stimulatory pathways enable fibroblasts stimulate CD4+ T cells. We use dynamic single cell RNA sequencing, spatial transcriptomics and gene editing technologies, to probe the regulatory networks that control fibroblast transition to cancer antigen presenting cells with T cell priming capabilities.
Cancer models for drug screening and research
There is an unmet need to develop precision human cancer modeling tools for clinical and research use. Current approaches are limited to static measurements in patient-derived samples. Real-time monitoring of primary tumors in settings that recapitulate the complex and dynamic tumor-host interactions, through appropriate dynamic model systems is lacking. We aim i) to customize established microfluidics-based platforms, i.e. tumor-chips, to culture primary human tumor specimens ii) to develop humanized patient-derived xenografts (PDX), and use them to study oncoimmunology mechanisms and screen therapies.