PolyI:C and CpG Synergize with Anti-ErbB2 mAb for Treatment of Breast Tumors Resistant to Immune Checkpoint Inhibitors

Cancer Res. 2017 Jan 15;77(2):312-319. doi: 10.1158/0008-5472.CAN-16-1873. Epub 2016 Nov 21.

Abstract

Innate and adaptive immune cells play an important role in the therapeutic activity of anti-ErbB2 mAbs, such as trastuzumab. In the clinic, breast tumors poorly infiltrated with immune cells are more resistant to trastuzumab, and patients have a worse prognosis. Because type I and II IFNs are critical to the immune-mediated activity of anti-ErbB2 mAb, we investigated the effect of combining polyI:C and CpG with trastuzumab-like therapy in immunocompetent mouse models of ErbB2+ breast cancer. We demonstrated that in situ delivery of polyI:C and CpG combined to systemic anti-ErbB2 mAb triggered a potent inflammatory response in breast tumors able to induce long-lasting CD8+ T cell-dependent antitumor immunity. Remarkably, polyI:C and CpG was superior to combined PD-1/CTLA-4 blockade in sensitizing tumors to anti-ErbB2 mAb therapy. Local injection of CpG and polyI:C in a primary tumor significantly enhanced the activity of systemic anti-ErbB2 mAb against a distant untreated tumor. Type I and II IFNs, as well as natural killer cells and CD8+ T cells, were indispensible to the synergistic activity of the combination treatment. Because synthetic RNA analogues and CpG oligodeoxynucleotides have been safely used in clinical trials, our study supports combination treatments with anti-ErbB2 mAbs. Cancer Res; 77(2); 312-9. ©2016 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / pharmacology*
  • CTLA-4 Antigen / antagonists & inhibitors
  • Female
  • Interferon Inducers / immunology
  • Interferon Inducers / pharmacology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Mammary Neoplasms, Animal / immunology
  • Mammary Neoplasms, Animal / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Oligodeoxyribonucleotides / immunology
  • Oligodeoxyribonucleotides / pharmacology*
  • Poly I-C / immunology
  • Poly I-C / pharmacology*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Real-Time Polymerase Chain Reaction
  • Receptor, ErbB-2 / antagonists & inhibitors

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • CPG-oligonucleotide
  • CTLA-4 Antigen
  • Interferon Inducers
  • Oligodeoxyribonucleotides
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Erbb2 protein, mouse
  • Receptor, ErbB-2
  • Poly I-C

Grant support