Epigenetic Stability of Exhausted T Cells Limits Durability of Reinvigoration by PD-1 Blockade

Overview

Journal Science

Specialty Science

Date 2016 Oct 30

PMID 27789795

Citations 659

Authors

Kristen E Pauken

Morgan A Sammons

Pamela M Odorizzi

Sasikanth Manne

Jernej Godec

Omar Khan

Adam M Drake

Zeyu Chen

Debattama R Sen

Makoto Kurachi

R Anthony Barnitz

Caroline Bartman

Bertram Bengsch

Alexander C Huang

Jason M Schenkel

Golnaz Vahedi

W Nicholas Haining

Shelley L Berger

E John Wherry

Affiliations

Soon will be listed here.

Abstract

Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (T) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram T into durable memory T cells (T) is unclear. We found that reinvigoration of T in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated T became reexhausted if antigen concentration remained high and failed to become T upon antigen clearance. T acquired an epigenetic profile distinct from that of effector T cells (T) and T cells that was minimally remodeled after PD-L1 blockade. This finding suggests that T are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the T epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.

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