Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma

Cancer Res. 2019 Mar 15;79(6):1113-1123. doi: 10.1158/0008-5472.CAN-18-1722. Epub 2019 Jan 23.


Identifying controlling features of responsiveness to checkpoint blockade therapies is an urgent goal in oncology research. Our group and others have previously shown melanoma tumors resistant to checkpoint blockade display features of mesenchymal transition, including E-cadherin loss. Here, we present the first in vivo evidence that E-cadherin from tumor cells facilitate immune attack, using a B16F10 melanoma mouse model in which E-cadherin is exogenously expressed (B16.Ecad). We find, compared with vector control, B16.Ecad exhibits delayed tumor growth, reduced metastatic potential, and increased overall survival in vivo. Transplantation of B16.Ecad into Rag1-/- and CD103-/- mice abrogated the tumor growth delay. This indicates the anti-melanoma response against B16.Ecad is both immune and CD103+ mediated. Moreover, B16.Ecad showed increased responsiveness to combination immune checkpoint blockade (ICB) compared with vector control. This work establishes a rationale for ICB responses observed in high E-cadherin-expressing tumors and suggests therapeutic advancement through amplifying CD103+ immune cell subsets.Significance: These findings identify the mechanism behind checkpoint blockade resistance observed in melanoma that has undergone mesenchymal transition and suggest activation of CD103+ immune cells as a therapeutic strategy against other E-cadherin-expressing malignancies.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/6/1113/F1.large.jpg.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Antineoplastic Agents, Immunological / pharmacology*
  • Apoptosis
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Cadherins / antagonists & inhibitors
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Cycle Checkpoints / drug effects*
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Integrin alpha Chains / genetics
  • Integrin alpha Chains / metabolism*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology*
  • Mice
  • Tumor Cells, Cultured
  • Tumor Microenvironment


  • Antigens, CD
  • Antineoplastic Agents, Immunological
  • Cadherins
  • Integrin alpha Chains
  • alpha E integrins