AUTHOR=Gong Chang , Anders Robert A. , Zhu Qingfeng , Taube Janis M. , Green Benjamin , Cheng Wenting , Bartelink Imke H. , Vicini Paolo , Wang Bing , Popel Aleksander S. TITLE=Quantitative Characterization of CD8+ T Cell Clustering and Spatial Heterogeneity in Solid Tumors JOURNAL=Frontiers in Oncology VOLUME=8 YEAR=2019 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00649 DOI=10.3389/fonc.2018.00649 ISSN=2234-943X ABSTRACT=

Quantitative characterization of the tumor microenvironment, including its immuno-architecture, is important for developing quantitative diagnostic and predictive biomarkers, matching patients to the most appropriate treatments for precision medicine, and for providing quantitative data for building systems biology computational models able to predict tumor dynamics in the context of immune checkpoint blockade therapies. The intra- and inter-tumoral spatial heterogeneities are potentially key to the understanding of the dose-response relationships, but they also bring challenges to properly parameterizing and validating such models. In this study, we developed a workflow to detect CD8+ T cells from whole slide imaging data, and quantify the spatial heterogeneity using multiple metrics by applying spatial point pattern analysis and morphometric analysis. The results indicate a higher intra-tumoral heterogeneity compared with the heterogeneity across patients. By comparing the baseline metrics with PD-1 blockade treatment outcome, our results indicate that the number of high-density T cell clusters of both circular and elongated shapes are higher in patients who responded to the treatment. This methodology can be applied to quantitatively characterize the tumor microenvironment, including immuno-architecture, and its heterogeneity for different cancer types.