Identifying the Spatial Architecture That Restricts the Proximity of CD8⁺ T Cells to Tumor Cells in Pancreatic Ductal Adenocarcinoma

The proximity to tumor cells is pivotal to the anti-tumor functions of CD8(+) T cells, but the mechanism underlying the regulation of CD8(+) T cell spatial distribution remains elusive. Here, we utilize the cellular neighborhood algorithm to identify the spatial architectures that regulate the localization and inter-cellular communication of CD8(+) T cells in human pancreatic ductal adenocarcinoma. The presence of CD8(+) T cells, CD4(+) T cells, and other lymphocytes in the same cellular neighborhoods were identified as one type of spatial architecture that restricted the proximity of CD8(+) T cells to tumor cells and heralded a poor prognosis. In such architecture, CD8(+) T cells tended to aggregate around themselves and CD4(+) T cells instead of approaching tumor cells. In this study, we identified a spatial architecture for the regulation of CD8(+) T cells and deciphered a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner. The anti-tumor function of CD8(+) T cells is dependent on their proximity to tumor cells. Current studies have focused on the infiltration level of CD8(+) T cells in the tumor microenvironment, while further spatial information, such as spatial localization and inter-cellular communication, have not been defined. In this study, co-detection by indexing (CODEX) was designed to characterize PDAC tissue regions with seven protein markers in order to identify the spatial architecture that regulates CD8(+) T cells in human pancreatic ductal adenocarcinoma (PDAC). The cellular neighborhood algorithm was used to identify a total of six conserved and distinct cellular neighborhoods. Among these, one unique spatial architecture of CD8(+) T and CD4(+) T cell-enriched neighborhoods enriched the majority of CD8(+) T cells, but heralded a poor prognosis. The proximity analysis revealed that the CD8(+) T cells in this spatial architecture were significantly closer to themselves and the CD4(+) T cells than to the tumor cells. Collectively, we identified a unique spatial architecture that restricted the proximity of CD8(+) T cells to tumor cells in the tumor microenvironment, indicating a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner and providing new insights into the biology of PDAC.