Therapeutic efficacy of PD-L1 blockade in a breast cancer model is enhanced by cellular vaccines expressing B7-1 and glycolipid-anchored IL-12

Hum Vaccin Immunother. 2016;12(2):421-30. doi: 10.1080/21645515.2015.1076953.

Abstract

Immunotherapeutic approaches have emerged as promising strategies to treat various cancers, including breast cancer. A single approach, however, is unlikely to effectively combat the complex, immune evasive strategies found within the tumor microenvironment, thus novel, effective combination treatments must be explored. In this study, we investigated the efficacy of a combination therapy consisting of PD-L1 immune checkpoint blockade and whole cell vaccination in a HER-2 positive mouse model of breast cancer. We demonstrate that tumorigenicity is completely abrogated when adjuvanted with immune stimulatory molecules (ISMs) B7-1 and a cell-surface anchored (GPI) form of IL-12 or GM-CSF. Irradiated cellular vaccines expressing the combination of adjuvants B7-1 and GPI-IL-12 completely inhibited tumor formation which was correlative with robust HER-2 specific CTL activity. However, in a therapeutic setting, both cellular vaccination and PD-L1 blockade induced only 10-20% tumor regression when administered alone but resulted in 50% tumor regression as a combination therapy. This protection was significantly hindered following CD4 or CD8 depletion indicating the essential role played by cellular immunity. Collectively, these pre-clinical studies provide a strong rationale for further investigation into the efficacy of combination therapy with tumor cell vaccines adjuvanted with membrane-anchored ISMs along with PD-L1 blockade for the treatment of breast cancer.

Keywords: GPI-anchored proteins; HER-2; PD-L1 blockade; breast cancer; immunotherapy; tumor cell vaccines.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B7-1 Antigen / immunology*
  • B7-H1 Antigen / antagonists & inhibitors*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / immunology*
  • Cell Line, Tumor
  • Female
  • Glycolipids / immunology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Immunity, Cellular / drug effects
  • Immunotherapy
  • Interleukin-12 / immunology*
  • Lymphocyte Depletion
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Receptor, ErbB-2 / metabolism
  • Tumor Microenvironment / immunology

Substances

  • B7-1 Antigen
  • B7-H1 Antigen
  • Cancer Vaccines
  • Cd274 protein, mouse
  • Glycolipids
  • Interleukin-12
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Erbb2 protein, mouse
  • Receptor, ErbB-2