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T FR Cells Inhibit Anti-Tumor Immunity and are Responsive to Immune Checkpoint Blockade

52 Pages Posted: 13 May 2020 Sneak Peek Status: Under Review

See all articles by Simon Eschweiler

Simon Eschweiler

La Jolla Institute for Immunology

James Clarke

La Jolla Institute for Immunology

Ciro Ramirez Suastegui

La Jolla Institute for Immunology

Bharat Panwar

La Jolla Institute for Immunology

Ariel Madrigal

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

Serena Chee

University of Southampton

Ioannis Karydis

University of Southampton

Edwin Woo

Southampton University Hospitals NHS Foundation Trust

Aiman Alzetani

Southampton University Hospitals NHS Foundation Trust

Somaia Elsheikh

University of Nottingham

C.J. Hanley

University of Southampton

G. J. Thomas

University of Southampton

Peter Friedmann

University of Southampton - Department of Clinical and Experimental Sciences

Tilman Sanchez-Elsner

University of Southampton

Ferhat Ay

La Jolla Institute for Allergy and Immunology (LIAI); University of California, San Diego (UCSD) - School of Medicine

Christian Ottensmeier

La Jolla Institute for Immunology

Pandurangan Vijayanand

La Jolla Institute for Immunology

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Abstract

Immune checkpoint blockade (ICB) has shown remarkable clinical success in boosting anti-tumor immunity. However, the breadth of its cellular targets and specific mode of action remain elusive. We find that T follicular regulatory (TFR) cells are present in high numbers in multiple tumors, inhibit anti-tumor immunity and are responsive to ICB. TCR-seq data, trajectory analyses and adoptive transfer studies indicate intratumoral TREG to TFR cell conversion. When compared to TREG cells, TFR cells exhibited enhanced suppressive capacity. In syngeneic tumor models, anti-PD-1 treatment increased the number of tumor-infiltrating TFR cells. Conditional knockout of TFR cells or depletion of TFR cells with anti-CTLA-4 antibody prior to anti-PD-1 treatment, improved tumor control in mice. Notably, in a cohort of melanoma patients, treatment with anti-CTLA-4 followed by anti-PD-1 at progression was associated with better long-term survival outcomes than anti-PD-1 or anti-CTLA-4 monotherapy, anti-PD-1 followed by anti CTLA-4 at progression or concomitant combination therapy.

Keywords: TFR cells, TREG cells, single-cell RNA-seq, Immune checkpoint blockade (ICB), CTLA-4, PD-1, sequential therapy, NSCLC, HNSCC, Melanoma

Suggested Citation

Eschweiler, Simon and Clarke, James and Ramirez Suastegui, Ciro and Panwar, Bharat and Madrigal, Ariel and Chee, Serena and Karydis, Ioannis and Woo, Edwin and Alzetani, Aiman and Elsheikh, Somaia and Hanley, C.J. and Thomas, G. J. and Friedmann, Peter and Sanchez-Elsner, Tilman and Ay, Ferhat and Ottensmeier, Christian and Vijayanand, Pandurangan, T FR Cells Inhibit Anti-Tumor Immunity and are Responsive to Immune Checkpoint Blockade. Available at SSRN: https://ssrn.com/abstract=3596586 or http://dx.doi.org/10.2139/ssrn.3596586
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Simon Eschweiler

La Jolla Institute for Immunology ( email )

La Jolla, CA
United States

James Clarke

La Jolla Institute for Immunology

La Jolla, CA
United States

Ciro Ramirez Suastegui

La Jolla Institute for Immunology

La Jolla, CA
United States

Bharat Panwar

La Jolla Institute for Immunology

La Jolla, CA
United States

Ariel Madrigal

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

La Jolla, CA 92037
United States

Serena Chee

University of Southampton

University Rd.
Southampton SO17 1BJ, Hampshire SO17 1LP
United Kingdom

Ioannis Karydis

University of Southampton

University Rd.
Southampton SO17 1BJ, Hampshire SO17 1LP
United Kingdom

Edwin Woo

Southampton University Hospitals NHS Foundation Trust

Southampton
United Kingdom

Aiman Alzetani

Southampton University Hospitals NHS Foundation Trust

Southampton
United Kingdom

Somaia Elsheikh

University of Nottingham

University Park
Nottingham, NG8 1BB
United Kingdom

C.J. Hanley

University of Southampton

University Rd.
Southampton SO17 1BJ, Hampshire SO17 1LP
United Kingdom

G. J. Thomas

University of Southampton

University Rd.
Southampton SO17 1BJ, Hampshire SO17 1LP
United Kingdom

Peter Friedmann

University of Southampton - Department of Clinical and Experimental Sciences

United Kingdom

Tilman Sanchez-Elsner

University of Southampton

University Rd.
Southampton SO17 1BJ, Hampshire SO17 1LP
United Kingdom

Ferhat Ay

La Jolla Institute for Allergy and Immunology (LIAI)

9420 Athena Cir
La Jolla, CA 92037
United States

University of California, San Diego (UCSD) - School of Medicine

9500 Gilman Drive
MC 0507
La Jolla, CA 92093
United States

Christian Ottensmeier

La Jolla Institute for Immunology

La Jolla, CA
United States

Pandurangan Vijayanand (Contact Author)

La Jolla Institute for Immunology ( email )

La Jolla, CA
United States

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