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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

67 Pages Posted: 2 Jul 2020 Publication Status: Review Complete

See all articles by Kelli Connolly

Kelli Connolly

Yale University - Department of Immunobiology

Manik Kuchroo

Yale University - Department of Genetics and Computer Science

Aarthi Venkat

Yale University - Computational Biology and Bioinformatics Program

Achia Khatun

Medical College of Wisconsin - Department of Microbiology and Immunology

Brittany Fitzgerald

Yale University - Department of Immunobiology

Martina Damo

Yale University - Department of Immunobiology

Moujtaba Y. Kasmani

Medical College of Wisconsin - Department of Microbiology and Immunology

Can Cui

Yale University - Department of Immunobiology

Isabel Monroy

Yale University - Department of Immunobiology

Amanda Hutchins

Yale University - Department of Immunobiology

Weiguo Cui

Medical College of Wisconsin - Department of Microbiology and Immunology

Smita Krishnaswamy

Yale University - Department of Genetics

Nikhil S. Joshi

Yale University - Department of Immunobiology

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Abstract

Intratumoral stem-like CD8+ T cells (TSL) are necessary for immunotherapeutic efficacy. Yet, tumors are rich in signals driving terminal differentiation of TSL cells into exhausted T cells. Using the “KP-NINJA” lung tumor model, we determined that tumor-specific TSL cells terminally differentiate in tumors, but that they are maintained by a reservoir of TSL cells from the tumor-draining lymph node (dLN). By tracing clones of tumor-specific CD8+ T cells using single-cell RNA/TCRseq, we found that dLN TSL cells were the developmental precursors of the more differentiated intratumoral T cell populations. Moreover, dLN TSL cells were developmentally stable over the disease course and blocking egress from dLNs resulted in a decrease in intratumoral TSL cells. Thus, we propose that the dLN reservoir protects the overall tumor-specific T cell population from terminal differentiation, allowing for prolonged responses under conditions of chronic antigen exposure. Future immunotherapeutic strategies could leverage this reservoir for anti-tumor effects.

Suggested Citation

Connolly, Kelli and Kuchroo, Manik and Venkat, Aarthi and Khatun, Achia and Fitzgerald, Brittany and Damo, Martina and Kasmani, Moujtaba Y. and Cui, Can and Monroy, Isabel and Hutchins, Amanda and Cui, Weiguo and Krishnaswamy, Smita and Joshi, Nikhil S., A Reservoir of Stem-Like CD8 T Cells in the Tumor-Draining Lymph Node Maintains the Ongoing Anti-Tumor Immune Response. Available at SSRN: https://ssrn.com/abstract=3640763
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Kelli Connolly

Yale University - Department of Immunobiology ( email )

300 Cedar Street
New Haven, CT 06520
United States

Manik Kuchroo

Yale University - Department of Genetics and Computer Science ( email )

333 Cedar Street
New Haven, CT 06520
United States

Aarthi Venkat

Yale University - Computational Biology and Bioinformatics Program ( email )

New Haven, CT 06520
United States

Achia Khatun

Medical College of Wisconsin - Department of Microbiology and Immunology ( email )

BSB - 2nd Floor - Room 273
8701 Watertown Plank Road
Milwaukee, WI 53226
United States

Brittany Fitzgerald

Yale University - Department of Immunobiology ( email )

300 Cedar Street
New Haven, CT 06520
United States

Martina Damo

Yale University - Department of Immunobiology ( email )

300 Cedar Street
New Haven, CT 06520
United States

Moujtaba Y. Kasmani

Medical College of Wisconsin - Department of Microbiology and Immunology ( email )

BSB - 2nd Floor - Room 273
8701 Watertown Plank Road
Milwaukee, WI 53226
United States

Can Cui

Yale University - Department of Immunobiology ( email )

300 Cedar Street
New Haven, CT 06520
United States

Isabel Monroy

Yale University - Department of Immunobiology ( email )

300 Cedar Street
New Haven, CT 06520
United States

Amanda Hutchins

Yale University - Department of Immunobiology ( email )

300 Cedar Street
New Haven, CT 06520
United States

Weiguo Cui

Medical College of Wisconsin - Department of Microbiology and Immunology ( email )

BSB - 2nd Floor - Room 273
8701 Watertown Plank Road
Milwaukee, WI 53226
United States

Smita Krishnaswamy

Yale University - Department of Genetics ( email )

333 Cedar Street
New Haven, CT 06520
United States

Nikhil S. Joshi (Contact Author)

Yale University - Department of Immunobiology

300 Cedar Street
New Haven, CT 06520
United States

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