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

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 T_REG to T_FR cell conversion. When compared to T_REG cells, T_FR cells exhibited enhanced suppressive capacity. In syngeneic tumor models, anti-PD-1 treatment increased the number of tumor-infiltrating T_FR cells. Conditional knockout of T_FR cells or depletion of T_FR 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