Immunity
Volume 54, Issue 10, 12 October 2021, Pages 2338-2353.e6
Journal home page for Immunity

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

https://doi.org/10.1016/j.immuni.2021.08.026Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Longitudinal scRNA-seq of tumor-specific TCF-1+ CD8+ T cells in KP lung adenocarcinoma

  • Identified a proliferative Slamf6+ TCF-1+ T cell subset and a non-cycling SlamF6 subset

  • The lymph node contains a recruitable reservoir of functional TCF-1+ CD8+ T cells

  • Flt3L+CD40 boosts cDC1, increases TCF-1+CD8+ T cell frequencies, decreases tumor burden

Summary

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.

Keywords

TCF-1+
CD8 T cells
T cell dysfunction
tumor immunology
tumor-draining lymph node
single-cell RNA-seq
migratory cDC1
Flt3L
anti-CD40

Data and code availability

Original single-cell RNA-seq data have been deposited at GEO and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. This paper also analyzes existing, publicly available data. These accession numbers for the datasets are listed in the key resources table. All original code has been deposited on Github and is publicly available as of the date of this publication. DOIs are listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Cited by (0)

12

Present address: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA

13

Present address: Immunai, 180 Varick St, New York, NY 10014, USA

14

Present address: Soleus Capital, 11 Elery St, Cambridge, MA 02138, USA

15

These authors contributed equally

16

These authors contributed equally

17

Senior author

18

Lead contact