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

Immunity. 2021 Oct 12;54(10):2338-2353.e6. doi: 10.1016/j.immuni.2021.08.026. Epub 2021 Sep 16.

Authors

Jason M Schenkel¹, Rebecca H Herbst², David Canner³, Amy Li⁴, Michelle Hillman⁵, Sean-Luc Shanahan⁵, Grace Gibbons⁵, Olivia C Smith⁵, Jonathan Y Kim⁵, Peter Westcott⁵, William L Hwang⁶, William A Freed-Pastor⁷, George Eng⁸, Michael S Cuoco⁹, Patricia Rogers⁹, Jin K Park¹⁰, Megan L Burger⁵, Orit Rozenblatt-Rosen⁹, Le Cong¹¹, Kristen E Pauken¹², Aviv Regev¹³, Tyler Jacks¹⁴

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
² Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
⁴ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
⁵ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
⁶ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Radiation Oncology, Massachusetts General Hospital, Boston MA 02114.
⁷ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
¹⁰ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
¹¹ Departments of Pathology, Stanford University, Stanford, CA 94305, USA.
¹² Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
¹³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: aviv.regev.sc@gmail.com.
¹⁴ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: tjacks@mit.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenocarcinoma of Lung / immunology*
Animals
CD8-Positive T-Lymphocytes / immunology*
Dendritic Cells / immunology*
Lung Neoplasms / immunology*
Lymph Nodes / immunology*
Mice
T Cell Transcription Factor 1 / immunology*
T-Lymphocyte Subsets / immunology

Substances

T Cell Transcription Factor 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding