Spatially resolved, single cell biomarkers of B cell lymphoma

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Project Summary/Abstract Diffuse Large B-Cell Lymphoma (DLBCL) is the most common form of Non-Hodgkin Lymphoma (NHL). DLBCL tumors are highly heterogeneous and molecular profiling has revealed up to six distinct prognostically relevant sub-groups, however these classifications are primarily based on profiles of the malignant cells. Non-malignant cells in the tumor immune microenvironment (TME) can be powerful modulators of tumor growth and can be targeted for cancer therapy, yet biomarkers that include TME elements have not been developed. We hypothesize that successful development of next generation immune targeting therapies for lymphoma will require spatially resolved, highly multiplexed single cell based biomarkers of TME composition and structure. In this study we propose to perform imaging mass cytometry analysis (IMC) on over 2000 cases of aggressive B cell lymphoma with the following aims: Specific Aim 1: Validate spatially-derived protein biomarkers of DLBCL outcomes (n-830 patients). Specific Aim 2: Analyze the single cell topology of histologically diverse aggressive B cell lymphomas (n=1380) to identify shared TME based biomarkers across all aggressive B cell lymphoma. Specific Aim 3: Determine which TME elements modulate chemoresistance and mediate response to immune therapies in lymphoma through in vitro model systems. In the first two Aims, we will apply our novel abundance weighted score (M-score), developed specifically for IMC analysis, to validate candidate biomarkers (such as PD-L1+/CCR4+/TIM-3+) and identify new biomarkers. We will also apply our single cell spatial clustering algorithm, Regions of Immune Cell Organization (RICO), to identify tumor-immune spatial clusters that are associated with clinical outcome. The spatial resolved, single cell, highly multiplexed, digital image analysis proposed here will have clinical impact for the ~80,000 new US cases of NHL. Specific Aim 1 will validate and discover protein biomarkers in a image format familiar to pathologists allowing for seamless clinical adoption, Specific Aim 2 will refine methods for spatial systems biology applied to challenging lymphoma types, and Specific Aim 3 will allow pre-clinical validation of prognostic and predictive biomarkers.