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.
Competing Interests: Declaration of interests T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific. He is also a co-founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. He is the President of Break Through Cancer. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. T.J. laboratory currently also receives funding from the Johnson & Johnson Lung Cancer Initiative and The Lustgarten Foundation for Pancreatic Cancer Research, but this funding did not support the research described in this manuscript. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov until July 31, 2020. From August 1, 2020, A.R. is an employee of Genentech.
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