Targeting the Tumor Microenvironment With interferon-β Bridges Innate and Adaptive Immune Responses

Cancer Cell. 2014 Jan 13;25(1):37-48. doi: 10.1016/j.ccr.2013.12.004.

Abstract

Antibodies (Abs) that preferentially target oncogenic receptors have been increasingly used for cancer therapy, but tumors often acquire intrinsic Ab resistance after prolonged and costly treatment. Herein we armed the Ab with IFNβ and observed that it is more potent than the first generation of Ab for controlling Ab-resistant tumors. This strategy controls Ab resistance by rebridging suppressed innate and adaptive immunity in the tumor microenvironment. Mechanistically, Ab-IFNβ therapy primarily and directly targets intratumoral dendritic cells, which reactivate CTL by increasing antigen cross-presentation within the tumor microenvironment. Additionally, blocking PD-L1, which is induced by Ab-IFNβ treatment, overcomes treatment-acquired resistance and completely eradicates established tumors. This study establishes a next-generation Ab-based immunotherapy that targets and eradicates established Ab-resistant tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity* / immunology
  • Animals
  • Antibodies / pharmacology
  • B7-H1 Antigen / immunology
  • Cell Line, Tumor
  • Cross-Priming / immunology
  • Dendritic Cells / immunology
  • Enzyme-Linked Immunosorbent Assay
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / immunology
  • Flow Cytometry
  • Immunity, Innate* / immunology
  • Immunotherapy / methods*
  • Interferon-beta / immunology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / immunology*
  • Tumor Microenvironment / immunology*

Substances

  • Antibodies
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Interferon-beta
  • EGFR protein, mouse
  • ErbB Receptors