Integrin αvβ8-expressing tumor cells evade host immunity by regulating TGF-β activation in immune cells

JCI Insight. 2018 Oct 18;3(20):e122591. doi: 10.1172/jci.insight.122591.


TGF-β is a promising immunotherapeutic target. It is expressed ubiquitously in a latent form that must be activated to function. Determination of where and how latent TGF-β (L-TGF-β) is activated in the tumor microenvironment could facilitate cell- and mechanism-specific approaches to immunotherapeutically target TGF-β. Binding of L-TGF-β to integrin αvβ8 results in activation of TGF-β. We engineered and used αvβ8 antibodies optimized for blocking or detection, which - respectively - inhibit tumor growth in syngeneic tumor models or sensitively and specifically detect β8 in human tumors. Inhibition of αvβ8 potentiates cytotoxic T cell responses and recruitment of immune cells to tumor centers - effects that are independent of PD-1/PD-L1. β8 is expressed on the cell surface at high levels by tumor cells, not immune cells, while the reverse is true of L-TGF-β, suggesting that tumor cell αvβ8 serves as a platform for activating cell-surface L-TGF-β presented by immune cells. Transcriptome analysis of tumor-associated lymphoid cells reveals macrophages as a key cell type responsive to β8 inhibition with major increases in chemokine and tumor-eliminating genes. High β8 expression in tumor cells is seen in 20%-80% of various cancers, which rarely coincides with high PD-L1 expression. These data suggest tumor cell αvβ8 is a PD-1/PD-L1-independent immunotherapeutic target.

Keywords: Cancer immunotherapy; Immunology; Integrins; Lung cancer; Macrophages.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor
  • Computer Simulation
  • Disease Models, Animal
  • Female
  • Humans
  • Integrins / antagonists & inhibitors
  • Integrins / metabolism*
  • Kaplan-Meier Estimate
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Neoplasms / drug therapy
  • Neoplasms / immunology*
  • Neoplasms / mortality
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Transforming Growth Factor beta / metabolism*
  • Tumor Escape / drug effects
  • Tumor Escape / immunology*
  • Tumor Microenvironment / immunology


  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • Integrins
  • Programmed Cell Death 1 Receptor
  • Transforming Growth Factor beta
  • integrin alphavbeta8