T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Academic Article uri icon

Overview

abstract

  • Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.

authors

  • Huang, Alexander C
  • Postow, Michael
  • Orlowski, Robert J
  • Mick, Rosemarie
  • Bengsch, Bertram
  • Manne, Sasikanth
  • Xu, Wei
  • Harmon, Shannon
  • Giles, Josephine R
  • Wenz, Brandon
  • Adamow, Matthew
  • Kuk, Deborah
  • Panageas, Katherine S
  • Carrera, Cristina
  • Wong, Phillip
  • Quagliarello, Felix
  • Wubbenhorst, Bradley
  • D'Andrea, Kurt
  • Pauken, Kristen E
  • Herati, Ramin S
  • Staupe, Ryan P
  • Schenkel, Jason M
  • McGettigan, Suzanne
  • Kothari, Shawn
  • George, Sangeeth M
  • Vonderheide, Robert H
  • Amaravadi, Ravi K
  • Karakousis, Giorgos C
  • Schuchter, Lynn M
  • Xu, Xiaowei
  • Nathanson, Katherine L
  • Wolchok, Jedd D
  • Gangadhar, Tara C
  • Wherry, E John

publication date

  • April 10, 2017

Research

keywords

  • CD8-Positive T-Lymphocytes
  • Melanoma
  • Programmed Cell Death 1 Receptor
  • Tumor Burden

Identity

PubMed Central ID

  • PMC5554367

Scopus Document Identifier

  • 85017451727

Digital Object Identifier (DOI)

  • 10.1038/nature22079

PubMed ID

  • 28397821

Additional Document Info

volume

  • 545

issue

  • 7652