Description

Monitoring Inflammation in Cancer by Multi-Plex in situ Imaging

Lisa M. Coussens

Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR, USA

Therapies targeting critical aspects of T cell regulation have revolutionized cancer therapy; however, many patients fail to respond and/or develop resistance. A major goal is to identify in situ or circulating biomarkers to aid patient stratification such that efficacy can be increased and expanded across tumor types. Profiling immune contexture is a powerful metric for tumor subclassification, and predicting clinical outcome.Based on this, we predicted that effective auditing of tumor leukocyte biomarkers in situ would provide sufficient stratification metrics with which to improve success of immune-based therapies. That said, we developed an optimized sequential immunohistochemistry approach, utilizing either biopsy or surgical specimens in FFPE tissue sections, and panels of antibodies enabling comprehensive phenotyping of immune complexity, together with computational image processing that support multiparameter cytometric quantification. These enable assessment of multiple lineage-selective and phenotypic biomarkers quantitatively evaluated with three 12-antibody biomarker panels, that together audit lymphoid and myeloid lineages, and functional status of T cells. Using this platform, we revealed differential immune complexity, representing either lymphoid- or myeloid-inflamed tumors, correlating with clinical outcomes and tumor subclassification in head and neck squamous cell carcinoma cohorts, and, by appending geometrical mapping analysis on top of leukocyte density, immune complexity status was linked to therapeutic response to vaccination therapy in pancreatic ductal adenocarcinoma, where myeloid-inflamed and T cell exhaustion status correlated with shorter overall survival. These advancements will expand biomarker-based discovery and deployment in oncoimmunology research, and improved ability to stratify and monitor patients receiving diverse immune-based therapeutics.

Support: NIH/NCI, Dept. of Defense Era of Hope Scholar Expansion Award, Susan G. Komen Fndt, Breast Cancer Research Fndt, Brenden-Colson Center for Pancreatic Health, and Stand Up To Cancer – Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant.