title: Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy.
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.
authors.affiliation: Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Christel
authors.initials: C
authors.lastname: Devaud
authors.affiliation: Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Westwood
authors.affiliation: Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Liza B
authors.initials: LB
authors.lastname: John
authors.affiliation: Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Flynn
authors.affiliation: Tumor Angiogenesis Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Sophie
authors.initials: S
authors.lastname: Paquet-Fifield
authors.affiliation: Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Connie P M
authors.initials: CP
authors.lastname: Duong
authors.affiliation: Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Carmen S M
authors.initials: CS
authors.lastname: Yong
authors.affiliation: Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Hollie J
authors.initials: HJ
authors.lastname: Pegram
authors.affiliation: Tumor Angiogenesis Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.affiliation: Tumor Angiogenesis Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
authors.affiliation: Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Trina J
authors.initials: TJ
authors.lastname: Stewart
authors.affiliation: Janssen Research and Development, Radnor, Pennsylvania, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Snyder
authors.affiliation: Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.affiliation: Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: 1] Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia [2] Department of Immunology, Monash University, Prahran, Victoria, Australia.
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
authors.affiliation: 1] Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia [2] Department of Immunology, Monash University, Prahran, Victoria, Australia.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000276:immunology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology; D004195:Disease Models, Animal; D015870:Gene Expression; D007167:Immunotherapy; D018793:Interleukin-13 / Q000276:immunology; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000276:immunology; D009928:Organ Specificity / Q000276:immunology; D011467:Prostate / Q000276:immunology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000276:immunology; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D018932:Chemokine CCL2; D018793:Interleukin-13; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
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