Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy
Christel Devaud1, Jennifer A Westwood1, Liza B John1
1Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
Abstract:
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.
Insights
Tumor location significantly impacts immunotherapy effectiveness. Orthotopic tumors show reduced response due to a suppressive microenvironment, unlike subcutaneous tumors, highlighting tissue-specific effects in cancer therapy.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- The tumor microenvironment (TME) influences tumor progression and treatment outcomes.
- Understanding how different anatomical sites affect TME and therapy response is crucial but largely unknown.
Purpose of the Study:
- To investigate the impact of anatomical location on tumor microenvironment and immunotherapy response.
- To compare the efficacy of a novel immunotherapy (Tri-mAb) in orthotopic versus subcutaneous tumor models.
Main Methods:
- Orthotopic and subcutaneous tumor models using renal, colon, and prostate cell lines.
- Ex vivo analysis of tumor cells and stromal cells.
- Immune profiling of TME, including macrophage and cytokine analysis.
- Therapeutic intervention using Tri-mAb and neutralizing antibodies for specific molecules.
Main Results:
- Orthotopic tumors exhibited significantly lower response to Tri-mAb immunotherapy compared to subcutaneous tumors.
- Orthotopic tumors displayed a type 2 immune response, immunosuppression, and increased vascularization.
- Alternatively activated macrophages and elevated chemokine (C-C motif) ligand 2 and interleukin-13 were observed in orthotopic kidney tumors.
- Neutralizing these factors improved therapeutic efficacy.
Conclusions:
- The tissue of implantation critically shapes the tumor microenvironment and influences therapeutic response.
- These findings underscore the importance of anatomical site in cancer biology and treatment strategy design.
- Further research into tissue-specific TME modulation is warranted for improved cancer therapies.
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