Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy

Mol Ther. 2014 Jan;22(1):18-27. doi: 10.1038/mt.2013.219. Epub 2013 Sep 19.


The tumor microenvironment can promote tumor growth and reduce treatment efficacy. Tumors can occur in many sites in the body, but how surrounding normal tissues at different anatomical sites affect tumor microenvironments and their subsequent response to therapy is not known.We demonstrated that tumors from renal, colon, or prostate cell lines in orthotopic locations responded to immunotherapy consisting of three agonist antibodies, termed Tri-mAb, to a much lesser extent than the same tumor type located subcutaneously. A tissue-specific response to Tri-mAb was confirmed by ex vivo separation of subcutaneous (SC) or orthotopic tumor cells from stromal cells, followed by reinjection of tumor cells into the opposite site. Compared with SC tumors, orthotopic tumors had a microenvironment associated with a type 2 immune response, related to immunosuppression, and an involvement of alternatively activated macrophages in the kidney model. Orthotopic kidney tumors were more highly vascularized than SC tumors. Neutralizing the macrophage- and Th2-associated molecules chemokine (C-C motif) ligand 2 or interleukin-13 led to a significantly improved therapeutic effect. This study highlights the importance of the tissue of implantation in sculpting the tumor microenvironment. These are important fundamental issues in tumor biology and crucial factors to consider in the design of experimental models and treatment strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • CD40 Antigens / antagonists & inhibitors
  • CD40 Antigens / immunology
  • Cell Line, Tumor
  • Chemokine CCL2 / immunology
  • Colonic Neoplasms / immunology
  • Disease Models, Animal
  • Gene Expression
  • Immunotherapy*
  • Interleukin-13 / immunology
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / mortality
  • Neoplasms / pathology*
  • Neoplasms / therapy
  • Neovascularization, Pathologic / immunology
  • Organ Specificity / immunology
  • Prostate / immunology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / immunology
  • Treatment Outcome
  • Tumor Microenvironment / immunology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / antagonists & inhibitors
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology


  • Antibodies, Monoclonal
  • CD40 Antigens
  • Chemokine CCL2
  • Interleukin-13
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor Receptor Superfamily, Member 9