Wolf et al. studied the impact on tumor development of a pro-healing microenvironment following co-injection of tumor cells with a decellularized urinary bladder extracellular matrix (UBM). UBM with several murine cancer cell lines slowed tumor development, dependent on CD4+ T cells and macrophages. B16F10 melanoma showed a type 2 immune signature characterized by IL-4-secreting Th2 CD4+ T cells, unique M2-type CD206+ macrophages, eosinophils, and improved response to PD-1 checkpoint therapy. A gene signature upregulated in UBM tumor T cells and macrophages correlated with improved survival in TCGA melanoma patients.
Contributed by Alex Najibi
Biomaterials in regenerative medicine are designed to mimic and modulate tissue environments to promote repair. Biologic scaffolds (derived from decellularized tissue extracellular matrix) promote a wound-healing (proregenerative) immune phenotype and are used clinically to treat tissue loss, including in the context of tumor resection. It is unknown whether a biomaterial microenvironment that encourages tissue formation may also promote tumor development. We implanted a urinary bladder matrix (UBM) scaffold, which is used clinically for wound management, with syngeneic cancer cell lines in mice to study how wound-healing immune responses affect tumor formation and sensitivity to immune checkpoint blockade. The UBM scaffold created an immune microenvironment that inhibited B16-F10 melanoma tumor formation in a CD4(+) T cell-dependent and macrophage-dependent manner. In-depth immune characterization revealed an activated type 2-like immune response that was distinct from the classical tumor microenvironment, including activated type 2 T helper T cells, a unique macrophage phenotype, eosinophil infiltration, angiogenic factors, and complement. Tumor growth inhibition by PD-1 and PD-L1 checkpoint blockade was potentiated in the UBM scaffold immune microenvironment. Engineering the local tumor microenvironment to promote a type 2 wound-healing immune signature may serve as a therapeutic target to improve immunotherapy efficacy.
Author Info: (1) Translational Tissue Engineering Center, Baltimore, MD 21231, USA. Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD 21287, USA. Department of Ophthalmology, J
Author Info: (1) Translational Tissue Engineering Center, Baltimore, MD 21231, USA. Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD 21287, USA. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (2) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD 21287, USA. Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (3) Translational Tissue Engineering Center, Baltimore, MD 21231, USA. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. (4) Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06511, USA. (5) David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. (6) Translational Tissue Engineering Center, Baltimore, MD 21231, USA. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. (7) Translational Tissue Engineering Center, Baltimore, MD 21231, USA. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. (8) Translational Tissue Engineering Center, Baltimore, MD 21231, USA. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. (9) University of Illinois College of Medicine, Chicago, IL 60612, USA. (10) Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (11) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD 21287, USA. Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (12) Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (13) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD 21287, USA. Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (14) Translational Tissue Engineering Center, Baltimore, MD 21231, USA. jhe@jhu.edu. Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD 21287, USA. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
