Abstract 2835: Effector T-cell shape is a potential digital biomarker for assessing CD8 lymphocyte activation in colorectal cancer (CRC) tumors

Abstract

Abstract With the recent advances in cancer immunotherapy it is critical to identify innovative biomarkers, reflecting the interaction between the tumor and its immune microenvironment. As a model system, CRC tumors are considered as non-immunogenic cancers with minor exception of microsatellite instable (MSI) cases that, in contrast to microsatellite stable (MSS) tumors, are characterized by a high tumor mutational burden (TMB) due to defects in mismatch repair (MMR) genes. These characteristics make MSI tumors more visible for the immune system, causing higher lymphocytic influx. When analyzing T cell kinetics, live cell imaging studies shown that T cells elongate while trafficking and are rounded while interacting or resting in the tissue. Based on these initial observations, we hypothesized that by assessing the density, distribution and shape of CD8 cytotoxic T cells in tumor areas, we could find a surrogate combined digital image-derived biomarker reflecting tumor immune microenvironment dynamics. To visualize this fundamental correlation, multiplexed immunohistochemistry was performed on 74 selected cases of primary CRC from our tissue bank collection with subsequent whole slide image analysis trained by machine learning. The CD8 T cell shape was assessed by nuclear eccentricity, along with PD1 and Ki67 activation status of the detected cell. Spatial plots revealed a haphazard T cell distribution in the overall tumor area, locating round and elongated CD8 T cells in both, tumor epithelium and tumor stroma compartments. Further discrimination of CD8 T cells according to PD1 and Ki67 positivity, showed higher activation / exhaustion in the round shaped T lymphocytes. In addition, we correlated the T cell shape with the MMR status and TMB assigned to the patient. Finally, integration of differential gene expression analysis provided insights into the role of the T cell shape in distinct tumor immune microenvironment conditions. With this novel approach, we discovered a new potential digital biomarker associated with the T effector cell function. Our results warrant further validation on bigger CRC patient cohorts, other tumor indications and through expanding the image analysis scope. Citation Format: Natalie Zwing, Xiao Li, Derrek Hibar, Henrik Failmezger, Yao Nie, Fabien Gaire, Konstanty Korski. Effector T-cell shape is a potential digital biomarker for assessing CD8 lymphocyte activation in colorectal cancer (CRC) tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2835.