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A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response

By Kelli A Connolly, Manik Kuchroo, Aarthi Venkat, Achia Khatun, Jiawei Wang, Ivana William, Noah Hornick, Brittany Fitzgerald, Martina Damo, Moujtaba Y Kasmani, Can Cui, Eric Fagerberg, Isabel Monroy, Amanda Hutchins, Julie F Cheung, Gena G Foster, Dylan L Mariuzza, Hongyu Zhao, Weiguo Cui, Smita Krishnaswamy, Nikhil S Joshi

Posted 27 Jan 2021
bioRxiv DOI: 10.1101/2021.01.27.428467

Stem-like TCF1+ CD8+ T cells (TSL) are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy but, as tumors contain signals that should drive T-cell terminal-differentiation, how these cells are maintained in tumors remains unclear. We found that a small number of TCF1+ tumor-specific CD8+ T cells were present in tumors throughout development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from hot to cold. By contrast, most tumor-specific CD8+ T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSL from chronic LCMV infection and this population was stable over time, despite the changes in the TME. dLN T cells were the precursors of their more-differentiated intratumoral counterparts, and maintenance of TCF1 by intratumoral T cells required continuous migration from dLNs. Finally, TSL CD8 T cells were also present in LNs from lung adenocarcinoma patients, suggesting this population is also relevant in human disease. Thus, we propose that the dLN TSL reservoir has a critical function during tumor development in sustaining antitumor T cells during tumor development and protecting them from the terminal differentiation that occurs in the TME.

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