title: Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming.
abstract: Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis. This paradox may be resolved by vessel normalization, which involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia. Although these processes alter tumour progression, their regulation is poorly understood. Here we show that type 1 T helper (TH1) cells play a crucial role in vessel normalization. Bioinformatic analyses revealed that gene expression features related to vessel normalization correlate with immunostimulatory pathways, especially T lymphocyte infiltration or activity. To delineate the causal relationship, we used various mouse models with vessel normalization or T lymphocyte deficiencies. Although disruption of vessel normalization reduced T lymphocyte infiltration as expected, reciprocal depletion or inactivation of CD4+T lymphocytes decreased vessel normalization, indicating a mutually regulatory loop. In addition, activation of CD4+T lymphocytes by immune checkpoint blockade increased vessel normalization. TH1 cells that secrete interferon-γ are a major population of cells associated with vessel normalization. Patient-derived xenograft tumours growing in immunodeficient mice exhibited enhanced hypoxia compared to the original tumours in immunocompetent humans, and hypoxia was reduced by adoptive TH1 transfer. Our findings elucidate an unexpected role of TH1 cells in vasculature and immune reprogramming. TH1 cells may be a marker and a determinant of both immune checkpoint blockade and anti-angiogenesis efficacy.
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Tian
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Goldstein
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Hin
authors.initials: H
authors.lastname: Ching Lo
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Ik
authors.initials: I
authors.lastname: Sun Kim
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Welte
authors.affiliation: Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Kuanwei
authors.initials: K
authors.lastname: Sheng
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Lacey E
authors.initials: LE
authors.lastname: Dobrolecki
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Nagireddy
authors.initials: N
authors.lastname: Putluri
authors.affiliation: Department of Pathology &Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Thuy L
authors.initials: TL
authors.lastname: Phung
authors.affiliation: Department of Translational Molecular Pathology, MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Sendurai A
authors.initials: SA
authors.lastname: Mani
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Stossi
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mancini
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Pathology &Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Decker
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Chenghang
authors.initials: C
authors.lastname: Zong
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lewis
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Xiang H-F
authors.initials: XH
authors.lastname: Zhang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D002199:Capillary Permeability; D015687:Cell Hypoxia / Q000502:physiology; D042783:Endothelial Cells / Q000276:immunology / Q000502:physiology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply* / Q000276:immunology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000276:immunology* / Q000502:physiology*; D020286:Pericytes / Q000166:cytology / Q000502:physiology; D011379:Prognosis; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
chemical_list: D007371:Interferon-gamma