Increased Dysfunction of Tumor Specific TCF-1+ CD8+ T Cells Associated with Increase in Non-Cycling TCF-1+ SlamF6- Cells Subsets Revealed by Single Cell Analysis

During chronic antigen stimulation, CD8+ T cells lose their effector potential. Because much of our understanding of anti-tumor T cell dysfunction comes from shorter-term transplantable models, it is less clear how dysfunction shifts over time in tumors. Using single-cell RNA-Seq and functional assays in an autochthonous model of lung adenocarcinoma, we demonstrate that anti-tumor CD8+ T cell dysfunction is dynamic and heterogeneous. In particular. we found a change over time in the composition of the TCF-1+ compartment, a population known to retain superior functionality, with proliferative TCF-1+ SlamF6+ cells predominant early, and an increase in non-cycling TCF-1+ SlamF6- cells with progression. Blocking egress from the draining lymph node decreased SlamF6+ CD8+ T cells in tumor-bearing lungs, suggesting that the lymph node is a reservoir of more functional anti-tumor CD8+ T cells. Collectively, our results provide insights into TCF-1+ T cell biology with therapeutic implications for anti-tumor immunity.