Glucocorticoid-induced TNF receptor family related protein (GITR) is present on many different cell types. Previous studies have shown that in vivo administration of an anti-GITR agonist mAb (DTA-1) inhibits regulatory T cells (Treg)-dependent suppression and enhances T cell responses. In this study, we show that administration of DTA-1 induces >85% tumor rejection in mice challenged with B16 melanoma. Rejection requires CD4+, CD8+, and NK1.1+ cells and is dependent on IFN-gamma and Fas ligand and independent of perforin. Depletion of Treg via anti-CD25 treatment does not induce B16 rejection, whereas 100% of the mice depleted of CD25+ cells and treated with DTA-1 reject tumors, indicating a predominant role of GITR on effector T cell costimulation rather than on Treg modulation. T cells isolated from DTA-1-treated mice challenged with B16 are specific against B16 and several melanoma differentiation Ags. These mice develop memory against B16, and a small proportion of them develop mild hypopigmentation. Consistent with previous studies showing that GITR stimulation increases Treg proliferation in vitro, we found in our model that GITR stimulation expanded the absolute number of FoxP3+ cells in vivo. Thus, we conclude that overall, GITR stimulation overcomes self-tolerance/ignorance and enhances T cell-mediated antitumor activity with minimal autoimmunity.
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"GITR ligation on T cells in vitro with endogenous or recombinant GITRL, mGITRL transfected cells, or agonist anti-GITR antibodies enhances IL-2Rα (CD25), IL-2 and IFNγ expression, cell proliferation and survival, especially in the context of a sub-optimal TCR signal [22,24252627. A protective role for GITR-mediated costimulation in T cell immunity was shown in experimental cancer therapy settings, in which GITR triggering enhanced CD8 T cell responses to tumor antigens with no or only limited autoimmunity282930. GITR stimulation in vitro also increases Treg numbers, enhances IL-10 production, and augments their suppressive capacity, which may contribute to immune homeostasis in vivo [31,32]. "
[Show abstract][Hide abstract]ABSTRACT: Author Summary
The ability of the immune system to rapidly respond to a viral infection is a prerequisite for the survival of an individual. The immediate reaction of innate immune cells and the subsequent response of antigen-specific lymphocytes is usually effective for rapid neutralization and removal of the invading virus. Yet, such protective immune responses need to be well controlled, as they can cause severe tissue damage that may disable the host more than the infection itself. One way that has evolutionarily been proven effective to deal with this balancing act between protective immunity and prevention of immunopathology is to render virus-specific T cells “exhausted” when the virus cannot be eradicated and the host becomes chronically infected. Exhausted T cells progressively lose their ability to kill other cells and produce different cytokines. The benefit of this exhausted state of anti-viral immunity is that it induces less tissue damage, but the downside is obviously less efficient control over the viral infection. Many immunotherapeutic and vaccination strategies against chronic viral infections are currently dedicated to overcome the exhausted state of the virus-specific T cells and thereby clear the virus. However, the accompanying risk is an exaggerated immune response with overt immunopathology. Here we describe in a mouse model that enhanced triggering through the costimulatory molecule GITR on T cells is able to provide protection upon viral infection and clear an otherwise persistent virus, but importantly without the development of collateral damage due to immunopathology. We show that GITR-mediated costimulation enhances a protective CD8 T cell response, for which CD4 T cell help is required. Our study provides new insights in how a particular costimulatory pathway can be utilized to boost anti-viral immunity, which is highly relevant for the development of safe immunotherapeutic strategies against chronic viral infections in humans.
"Extensive preclinical studies indicate that agonistic OX40 therapy can promote antitumor immunity by simultaneously expanding effector T cells while blocking Treg mediated suppression [75–80], particularly when delivered intratumourally . Similarly agonistic 4-1BB therapy may enhance tumor immunity by enhancing effector function and protecting it from programmed cell death [81, 82], while anti-GITR therapy has been associated with the ability to break tolerance to melanoma differentiation antigens  and augment Treg accumulation within tumors . Importantly, the antitumor potential of agonistic OX40, 4-1BB, and GITR immunotherapies can be significantly enhanced when combined with conventional cancer treatments such as chemotherapy, radiotherapy, surgery, or other immunotherapies [77, 85–87]. "
[Show abstract][Hide abstract]ABSTRACT: Most anticancer therapies including immunotherapies are given systemically; yet therapies given directly into tumorsmay be more effective, particularly those that overcomenatural suppressive factors in the tumor microenvironment.The“TrojanHorse” approach of intratumoural delivery aims to promote immune-mediated destruction by inducing microenvironmental changes within the tumour at the same time as avoiding the systemic toxicity that is often associated with more “full frontal” treatments such as transfer of large numbers of laboratory-expanded tumor-specific cytotoxic T lymphocytes or large intravenous doses of cytokine. Numerous studies have demonstrated that intratumoural therapy has the capacity to minimizing local suppression, inducing sufficient “dangerous” tumor cell death to cross-prime strong immune responses, and rending tumor blood vessels amenable to immune cell traffic to induce effector cell changes in secondary lymphoid organs. However, the key to its success is the design of a sound rational approach based on evidence. There is compelling preclinical data for local immunotherapy approaches in tumor
immunology. This review summarises how immune events within a tumour can be modified by local approaches, how this can affect systemic antitumor immunity such that distal sites are attacked, and what approaches have been proven most successful so far in animals and patients.
Full-text · Article · May 2014 · Research Journal of Immunology
"We also observed an
increased percentage of splenic CD8+ T cells in combined mAb-treated mice
compared with that in control or single mAb-treated mice (9.3 ± 3.1%, 10.3 ±
2.9%, 10.6 ± 3.0% or 13.1 ± 2.6% for control, anti-PD-1 or anti-OX40 or
anti-PD-1/OX40 group); after normalization to the percentage of splenic CD8+
T cells, a significantly increased mesothelin-specific IFN-γ production from
combined mAb-treated mice was still seen (data not shown). As an endogenous non-mutated
antigen, mesothelin should be naturally tolerized against; therefore, the induction of
mesothelin-specific CTL response by anti-PD-1/GITR mAb treatment indicates that
endogenous tolerance to mesothelin was broken, which is consistent with previous studies
demonstrating the overcome of tolerance/ignorance by GITR activation in murine tumors
and the presence of mesothelin-specific immune response in patients with cancers
expressing high level of mesothelin [24,35,36]. We did not detect mesothelin-specific antibodies in sera from mice treated
with combined mAb (data not shown). "
[Show abstract][Hide abstract]ABSTRACT: The coinhibitory receptor Programmed Death-1 (PD-1) inhibits effector functions of activated T cells and prevents autoimmunity, however, cancer hijack this pathway to escape from immune attack. The costimulatory receptor glucocorticoid-induced TNFR related protein (GITR) is up-regulated on activated T cells and increases their proliferation, activation and cytokine production. We hypothesize that concomitant PD-1 blockade and GITR triggering would synergistically improve the effector functions of tumor-infiltrating T cells and increase the antitumor immunity. In present study, we evaluated the antitumor effects and mechanisms of combined PD-1 blockade and GITR triggering in a clinically highly relevant murine ID8 ovarian cancer model.
Mice with 7 days-established peritoneal ID8 ovarian cancer were treated intraperitoneally (i.p.) with either control, anti-PD-1, anti-GITR or anti-PD-1/GITR monoclonal antibody (mAb) and their survival was evaluated; the phenotype and function of tumor-associated immune cells in peritoneal cavity of treated mice was analyzed by flow cytometry, and systemic antigen-specific immune response was evaluated by ELISA and cytotoxicity assay.
Combined anti-PD-1/GITR mAb treatment remarkably inhibited peritoneal ID8 tumor growth with 20% of mice tumor free 90 days after tumor challenge while treatment with either anti-PD-1 or anti-GITR mAb alone exhibited little antitumor effect. The durable antitumor effect was associated with a memory immune response and conferred by CD4+ cells and CD8+ T cells. The treatment of anti-PD-1/GITR mAb increased the frequencies of interferon-gamma-producing effector T cells and decreased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, shifting an immunosuppressive tumor milieu to an immunostimulatory state in peritoneal cavity. In addition, combined treatment of anti-PD-1/GITR mAb mounted an antigen-specific immune response as evidenced by antigen-specific IFN-gamma production and cytolytic activity of spleen cells from treated mice. More importantly, combined treatment of anti-PD-1/GITR mAb and chemotherapeutic drugs (cisplatin or paclitaxel) further increased the antitumor efficacy with 80% of mice obtaining tumor-free long-term survival in murine ID8 ovarian cancer and 4 T1 breast cancer models.
Combined anti-PD-1/GITR mAb treatment induces a potent antitumor immunity, which can be further promoted by chemotherapeutic drugs. A combined strategy of anti-PD-1/GITR mAb plus cisplatin or paclitaxel should be considered translation into clinic.
Full-text · Article · Feb 2014 · Journal of Translational Medicine