Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes

Abstract

In tumors, a subset of CD8⁺ T cells expressing the transcription factor TCF-1 drives the response to immune checkpoint blockade. We examined the mechanisms that maintain these cells in an autochthonous model of lung adenocarcinoma. Longitudinal sampling and single-cell sequencing of tumor-antigen specific TCF-1⁺ CD8⁺ T cells revealed that while intratumoral TCF-1⁺ CD8⁺ T cells acquired dysfunctional features and decreased in number as tumors progressed, TCF-1⁺ CD8⁺ T cell frequency in the tumor draining LN (dLN) remained stable. Two discrete intratumoral TCF-1⁺ CD8⁺ T cell subsets developed over time-a proliferative SlamF6⁺ subset and a non-cycling SlamF6^- subset. Blocking dLN egress decreased the frequency of intratumoral SlamF6⁺ TCF-1⁺ CD8⁺ T cells. Conventional type I dendritic cell (cDC1) in dLN decreased in number with tumor progression, and Flt3L+anti-CD40 treatment recovered SlamF6⁺ T cell frequencies and decreased tumor burden. Thus, cDC1s in tumor dLN maintain a reservoir of TCF-1⁺ CD8⁺ T cells and their decrease contributes to failed anti-tumor immunity.