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

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.