Abstract

One of the primary challenges in current cancer immunotherapy is the insufficient infiltration of cytotoxic T cells into solid tumors. Despite ongoing investigations, the mechanisms restricting T cell infiltration in immune-cold tumors remains elusive, hindered by the intricate tumor microenvironment. Here, we co-cultured mouse cancer cell lines with cancer-specific cytotoxic T cells to study the influence of cancer-T cell interactions on T cell motility, a crucial factor for effective tumor infiltration. By quantifying T cell motility patterns, we found that cancer-specific T cells exhibited extended contact time with cancer-cell clusters and higher directional persistence than non-specific T cells. Computational modelling suggested that T cells with stronger persistence could facilitate efficient searching for cancer clusters. Transcriptomic profiling revealed T cells recognizing cancer cells orchestrate accumulation on cancer cell clusters by activating adhesion proteins on both cancer cells and T cells, thereby fostering prolonged interaction on cancer cells. Furthermore, we observed that there were two distinct subpopulations of cancer cells after co-culturing with cancer-specific T cells: one expressing elevated levels of T-cell attractants and antigen-presentation molecules, while the other expressing immunosuppressive molecules and undergoing epithelial-to-mesenchymal transition. These dynamic insights into the complex interplay of cancer-T cell interactions and their impact on T cell motility hold implications for refining more efficacious cancer immunotherapy strategies.