title: GITR agonist enhances vaccination responses in lung cancer.
abstract: An immune tolerant tumor microenvironment promotes immune evasion of lung cancer. Agents that antagonize immune tolerance will thus aid the fight against this devastating disease. Members of the tumor necrosis factor receptor (TNFR) family modulate the magnitude, duration and phenotype of immune responsiveness to antigens. Among these, GITR expressed on immune cells functions as a key regulator in inflammatory and immune responses. Here, we evaluate the GITR agonistic antibody (DTA-1) as a mono-therapy and in combination with therapeutic vaccination in murine lung cancer models. We found that DTA-1 treatment of tumor-bearing mice increased: (i) the frequency and activation of intratumoral natural killer (NK) cells and T lymphocytes, (ii) the antigen presenting cell (APC) activity in the tumor, and (iii) systemic T-cell specific tumor cell cytolysis. DTA-1 treatment enhanced tumor cell apoptosis as quantified by cleaved caspase-3 staining in the tumors. DTA-1 treatment increased expression of IFNγ, TNFα and IL-12 but reduced IL-10 levels in tumors. Furthermore, increased anti-angiogenic chemokines corresponding with decreased pro-angiogenic chemokine levels correlated with reduced expression of the endothelial cell marker Meca 32 in the tumors of DTA-1 treated mice. In accordance, there was reduced tumor growth (8-fold by weight) in the DTA-1 treatment group. NK cell depletion markedly inhibited the antitumor response elicited by DTA-1. DTA-1 combined with therapeutic vaccination caused tumor rejection in 38% of mice and a 20-fold reduction in tumor burden in the remaining mice relative to control. Mice that rejected tumors following therapy developed immunological memory against subsequent re-challenge. Our data demonstrates GITR agonist antibody activated NK cell and T lymphocyte activity, and enhanced therapeutic vaccination responses against lung cancer.
authors.affiliation: Department of Medicine; UCLA Lung Cancer Research Program ; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA ; Molecular Gene Medicine Laboratory; Veterans Affairs Greater Los Angeles Healthcare System ; Los Angeles, CA USA.
authors.forename: Li X
authors.initials: LX
authors.lastname: Zhu
authors.affiliation: Molecular Gene Medicine Laboratory; Veterans Affairs Greater Los Angeles Healthcare System ; Los Angeles, CA USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Davoodi
authors.affiliation: Department of Medicine; UCLA Lung Cancer Research Program ; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA ; Molecular Gene Medicine Laboratory; Veterans Affairs Greater Los Angeles Healthcare System ; Los Angeles, CA USA.
authors.forename: Minu K
authors.initials: MK
authors.lastname: Srivastava
authors.affiliation: Department of Medicine; UCLA Lung Cancer Research Program ; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA ; Jonsson Comprehensive Cancer Center; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA.
authors.forename: Puja
authors.initials: P
authors.lastname: Kachroo
authors.affiliation: Department of Medicine; UCLA Lung Cancer Research Program ; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA ; Molecular Gene Medicine Laboratory; Veterans Affairs Greater Los Angeles Healthcare System ; Los Angeles, CA USA ; Jonsson Comprehensive Cancer Center; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA.
authors.forename: Jay M
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Medicine; UCLA Lung Cancer Research Program ; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA ; Jonsson Comprehensive Cancer Center; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA.
authors.forename: Maie
authors.initials: M
authors.lastname: St John
authors.affiliation: Molecular Gene Medicine Laboratory; Veterans Affairs Greater Los Angeles Healthcare System ; Los Angeles, CA USA.
authors.forename: Marni
authors.initials: M
authors.lastname: Harris-White
authors.affiliation: Department of Medicine; UCLA Lung Cancer Research Program ; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA ; Molecular Gene Medicine Laboratory; Veterans Affairs Greater Los Angeles Healthcare System ; Los Angeles, CA USA.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Medicine; University of Virginia ; Charlottesville, VA USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
authors.affiliation: Department of Medicine; UCLA Lung Cancer Research Program ; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA ; Molecular Gene Medicine Laboratory; Veterans Affairs Greater Los Angeles Healthcare System ; Los Angeles, CA USA ; Jonsson Comprehensive Cancer Center; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Dubinett
authors.affiliation: Department of Medicine; UCLA Lung Cancer Research Program ; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA ; Molecular Gene Medicine Laboratory; Veterans Affairs Greater Los Angeles Healthcare System ; Los Angeles, CA USA ; Jonsson Comprehensive Cancer Center; David Geffen School of Medicine at UCLA ; Los Angeles, CA USA.
authors.forename: Sherven
authors.initials: S
authors.lastname: Sharma
keywords: APC; APC, antigen presenting cell; Ab, antibody; BMA, bone marrow adherent; CTL, cytotoxic T lymphocyte; DC, dendritic cell; DTA-1, anti-GITR antibody; ERK, extracellular signal-regulated kinase; GITR, glucocorticoid‐induced TNFR‐related gene;IFNγ, interferon γ; JNK, janus kinase; MAPK, mitogen-activated protein kinase; MDSC, myeloid derived suppressor cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NK; NK, natural killer; P38, p38 mitogen-activated protein kinase(s); PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1;TNFα, Interferon Alpha; T cell activation; TCR, T cell receptor; TNFR, tumor necrosis factor receptor; Treg, regulatory T cell; lung cancer; vaccination responses