Abstract B65: Mathematical modeling studies on spatial profiles of tumor-infiltrating T cells
Authors: Gruosso Tina , Park Morag , Levine Herbert , Li Xuefei 
Published: June 2021

Abstract
Activated cytotoxic T lymphocytes have been demonstrated to be able to kill antigen-specific cancer cells via various mechanisms. Not surprisingly, stronger infiltration of cytotoxic T cells into tumor/tumor-cell clusters generally associates with better prognosis, which has been demonstrated in various cancers. There have been efforts on quantifying the distribution of cytotoxic T cells on the whole tumor level. On the other hand, a solid tumor is usually composed of many tumor-cell clusters as well as stroma in gaps between those clusters. It has been noticed that T cells can be mostly localized in the stromal regions of a solid tumor. Therefore, it is also important to quantify the spatial pattern of T cells on the tumor-cell cluster level and further investigate the mechanism underlying the observed limited infiltration. In our work, we quantified the spatial distribution of CD8+ T cells with respect to their distance to the boundary of individual tumor-cell clusters. Generally, we observed that: i) patients differ in infiltration at the cluster level; ii) for most samples, T cells mainly accumulate outside the tumor-cell clusters; iii) for some samples T cells can effectively infiltrate the tumor-cell clusters; and iv) for other samples, the T-cell infiltration profile is intermediate. This last possibility reveals a non-monotonic distribution of T cells, i.e., a drop of T-cell density at the boundary coupled with a second accumulation of T cells at the center of tumor-cell clusters. Based on the quantified CD8+ T-cell profiles on the tumor-cell cluster level, we constructed mathematical models to test two hypothesized contributors affecting the spatial distribution of CD8+ T cells: a physical motility barrier set up by the ECM fibers in the stroma and a biochemical inhibitor ultimately due to the cancer cells inside the tumor-cell clusters. Mathematical models that only include physical barrier effects can qualitatively capture some (but not all) spatial features of the T-cell profiles. However, there is one significant shortcoming: the physical barrier scenario predicts that the profiles observed should be transient and hence eventually T cells should infiltrate all tumors. This appears inconsistent with simple time-scale estimates. A biochemical model focusing on T-cell repulsion can give rise to the observed spatial profiles as steady-state solutions; the different patterns correspond to different properties of cancer cells in different patients. We therefore favor this modeling framework. Of course, a definitive test would require experiments that would enable us to study the infiltration of T cells in a time-dependent manner or alternatively perturb possible mechanisms with drugs to directly test their effects on the infiltration pattern of T cells.
Citation Format: Tina Gruosso, Morag Park, Herbert Levine, Xuefei Li. Mathematical modeling studies on spatial profiles of tumor-infiltrating T cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B65.