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

Jason M. Schenkel; Rebecca H. Herbst; David Canner; Amy Li; Michelle Hillman; Sean Luc Shanahan; Grace Gibbons; Olivia C. Smith; Jonathan Y. Kim; Peter Westcott; William L. Hwang; William A. Freed-Pastor; George Eng; Michael S. Cuoco; Patricia Rogers; Jin K. Park; Megan L. Burger; Orit Rozenblatt-Rosen; Le Cong; Kristen E. Pauken; Aviv Regev; Tyler Jacks

doi:10.1016/j.immuni.2021.08.026

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

Jason M. Schenkel, Rebecca H. Herbst, David Canner, Amy Li, Michelle Hillman, Sean Luc Shanahan, Grace Gibbons, Olivia C. Smith, Jonathan Y. Kim, Peter Westcott, William L. Hwang, William A. Freed-Pastor, George Eng, Michael S. Cuoco, Patricia Rogers, Jin K. Park, Megan L. Burger, Orit Rozenblatt-Rosen, Le Cong, Kristen E. PaukenAviv Regev, Tyler Jacks

Research output: Contribution to journal › Article › peer-review

107 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2338-2353.e6
Journal	Immunity
Volume	54
Issue number	10
DOIs	https://doi.org/10.1016/j.immuni.2021.08.026
State	Published - Oct 12 2021
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

Access to Document

10.1016/j.immuni.2021.08.026

Cite this

Schenkel, J. M., Herbst, R. H., Canner, D., Li, A., Hillman, M., Shanahan, S. L., Gibbons, G., Smith, O. C., Kim, J. Y., Westcott, P., Hwang, W. L., Freed-Pastor, W. A., Eng, G., Cuoco, M. S., Rogers, P., Park, J. K., Burger, M. L., Rozenblatt-Rosen, O., Cong, L., ... Jacks, T. (2021). Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1⁺ CD8⁺ T cells in tumor-draining lymph nodes. Immunity, 54(10), 2338-2353.e6. https://doi.org/10.1016/j.immuni.2021.08.026

Schenkel, JM, Herbst, RH, Canner, D, Li, A, Hillman, M, Shanahan, SL, Gibbons, G, Smith, OC, Kim, JY, Westcott, P, Hwang, WL, Freed-Pastor, WA, Eng, G, Cuoco, MS, Rogers, P, Park, JK, Burger, ML, Rozenblatt-Rosen, O, Cong, L, Pauken, KE, Regev, A & Jacks, T 2021, 'Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1⁺ CD8⁺ T cells in tumor-draining lymph nodes', Immunity, vol. 54, no. 10, pp. 2338-2353.e6. https://doi.org/10.1016/j.immuni.2021.08.026

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title = "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.",

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

author = "Schenkel, {Jason M.} and Herbst, {Rebecca H.} and David Canner and Amy Li and Michelle Hillman and Shanahan, {Sean Luc} and Grace Gibbons and Smith, {Olivia C.} and Kim, {Jonathan Y.} and Peter Westcott and Hwang, {William L.} and Freed-Pastor, {William A.} and George Eng and Cuoco, {Michael S.} and Patricia Rogers and Park, {Jin K.} and Burger, {Megan L.} and Orit Rozenblatt-Rosen and Le Cong and Pauken, {Kristen E.} and Aviv Regev and Tyler Jacks",

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day = "12",

doi = "10.1016/j.immuni.2021.08.026",

language = "English (US)",

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T1 - Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes

AU - Schenkel, Jason M.

AU - Herbst, Rebecca H.

AU - Canner, David

AU - Li, Amy

AU - Hillman, Michelle

AU - Shanahan, Sean Luc

AU - Gibbons, Grace

AU - Smith, Olivia C.

AU - Kim, Jonathan Y.

AU - Westcott, Peter

AU - Hwang, William L.

AU - Freed-Pastor, William A.

AU - Eng, George

AU - Cuoco, Michael S.

AU - Rogers, Patricia

AU - Park, Jin K.

AU - Burger, Megan L.

AU - Rozenblatt-Rosen, Orit

AU - Cong, Le

AU - Pauken, Kristen E.

AU - Regev, Aviv

AU - Jacks, Tyler

PY - 2021/10/12

Y1 - 2021/10/12

N2 - 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.

AB - 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.

KW - CD8 T cells

KW - Flt3L

KW - T cell dysfunction

KW - TCF-1+

KW - anti-CD40

KW - migratory cDC1

KW - single-cell RNA-seq

KW - tumor immunology

KW - tumor-draining lymph node

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U2 - 10.1016/j.immuni.2021.08.026

DO - 10.1016/j.immuni.2021.08.026

M3 - Article

C2 - 34534439

AN - SCOPUS:85115016953

SN - 1074-7613

VL - 54

SP - 2338-2353.e6

JO - Immunity

JF - Immunity

IS - 10

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