Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer

J Clin Invest. 2017 Sep 1;127(9):3472-3483. doi: 10.1172/JCI90499. Epub 2017 Aug 21.

Abstract

Claudin-low breast cancer is an aggressive subtype that confers poor prognosis and is found largely within the clinical triple-negative group of breast cancer patients. Here, we have shown that intrinsic and immune cell gene signatures distinguish the claudin-low subtype clinically as well as in mouse models of other breast cancer subtypes. Despite adaptive immune cell infiltration in claudin-low tumors, treatment with immune checkpoint inhibitory antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death receptor 1 (PD-1) were ineffective in controlling tumor growth. CD4+FoxP3+ Tregs represented a large proportion of the tumor-infiltrating lymphocytes (TILs) in claudin-low tumors, and Tregs isolated from tumor-bearing mice were able to suppress effector T cell responses. Tregs in the tumor microenvironment highly expressed PD-1 and were recruited partly through tumor generation of the chemokine CXCL12. Antitumor efficacy required stringent Treg depletion combined with checkpoint inhibition; delays in tumor growth were not observed using therapies that modestly diminished the number of Tregs in the tumor microenvironment. This study provides evidence that the recruitment of Tregs to the tumor microenvironment inhibits an effective antitumor immune response and highlights early Treg recruitment as a possible mechanism for the lack of response to immune checkpoint blockade antibodies in specific subtypes of cancer that are heavily infiltrated with adaptive immune cells.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CTLA-4 Antigen / metabolism
  • Cell Cycle Checkpoints*
  • Chemokine CXCL12 / metabolism
  • Claudins / metabolism*
  • Cluster Analysis
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Humans
  • Lymphocytes, Tumor-Infiltrating / cytology
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Mammary Neoplasms, Animal / drug therapy
  • Mammary Neoplasms, Animal / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • Programmed Cell Death 1 Receptor / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / immunology
  • Tumor Microenvironment

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Claudins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor