The overarching goal of this proposal is to build out an independent research group at MD Anderson addressing pressing questions focusing on the emergence of spatial heterogeneity in solid tumors that arise from cell-cell communication networks. We will use the fusion of novel transcriptomic, imaging, and computational methods that I have developed in my postdoctoral career to map these networks and how the effects of immunotherapies propagate unevenly due to tumor heterogeneity. Specifically, we will: Aim 1: Use spatial transcriptomics (ZipSeq) to map TCR sequences and gene expression signatures co-localized with regions of reinvigorated tumor cell killing following ICB treatment as well as ...

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The overarching goal of this proposal is to build out an independent research group at MD Anderson addressing pressing questions focusing on the emergence of spatial heterogeneity in solid tumors that arise from cell-cell communication networks. We will use the fusion of novel transcriptomic, imaging, and computational methods that I have developed in my postdoctoral career to map these networks and how the effects of immunotherapies propagate unevenly due to tumor heterogeneity. Specifically, we will: Aim 1: Use spatial transcriptomics (ZipSeq) to map TCR sequences and gene expression signatures co-localized with regions of reinvigorated tumor cell killing following ICB treatment as well as refractory regions. Target mechanisms that restrain local anti-tumor activity and determine relationship between TCR affinity and ICB mediated tumor killing. Aim 2: Identify mechanisms whereby the non-immune stroma influences the localization and state of immune cells pre and post ICB. Apply ZipSeq to colocalize fibroblast expression patterns with local immune cell gene expression to identify crosstalk mechanisms. Map immune cells in leaky and non-leaky perivascular niches. Use targets identified to perturb these stromal cells to create a more permissive environment for ICB’s effects to propagate. Aim 3: Translate candidate genes and crosstalk mechanisms from Aims 1+2 to patient samples, both fresh and banked from longitudinal, rapid immunotherapy studies. Apply ZipSeq to mapping cell states in regions of interest from fresh samples, while applying high-plex imaging with panels informed by discovery studies to find spatial patterns of gene expression that correlate with immunotherapy response. Ultimately my goal is to use the intersection of high dimensional transcriptomic space with the 3 dimensions of physical space to develop new clinical interventions that can synergize with existing immunotherapies and new spatially resolved prognostic measures for therapy response.

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