Rapid tolerization of virus-activated tumor-specific CD8
            <sup>+</sup>
            T cells in prostate tumors of TRAMP mice

Bai, Ailin; Higham, Eileen M.; Eisen, Herman N.; Wittrup, K. Dane; Chen, Jianzhu

doi:10.1073/pnas.0805599105

Cited by 64 publications

(89 citation statements)

References 37 publications

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“…Only a small fraction of the CD8 T cells expressed NKG2D, and the expression levels were not significantly different between TRAMP/ MICB and TRAMP mice. Given that NKG2D is only expressed by activated mouse CD8 T cells and that antigen-specific CD8 T cell tolerance is well documented in TRAMP mice (39,40), this observation is expected. Intriguingly, the frequency and absolute number of NK cells in the spleen were significantly reduced in TRAMP/ MICB mice that developed PD carcinomas and metastasis ( Figure 3B and Supplemental Figure 3B).…”

Section: Resultsmentioning

confidence: 89%

Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

et al. 2013

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The activating receptor NK cell group 2 member D (NKG2D) mediates antitumor immunity in experimental animal models. However, whether NKG2D ligands contribute to tumor suppression or progression clinically remains controversial. Here, we have described 2 novel lines of "humanized" bi-transgenic (bi-Tg) mice in which native human NKG2D ligand MHC class I polypeptide-related sequence B (MICB) or the engineered membrane-restricted MICB (MICB.A2) was expressed in the prostate of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous carcinogenesis. Bi-Tg TRAMP/MICB mice exhibited a markedly increased incidence of progressed carcinomas and metastasis, whereas TRAMP/MICB.A2 mice enjoyed long-term tumor-free survival conferred by sustained NKG2D-mediated antitumor immunity. Mechanistically, we found that cancer progression in TRAMP/MICB mice was associated with loss of the peripheral NK cell pool owing to high serum levels of tumor-derived soluble MICB (sMICB). Prostate cancer patients also displayed reduction of peripheral NK cells and high sMIC levels. Our study has not only provided direct evidence in "humanized" mouse models that soluble and membrane-restricted NKG2D ligands pose opposite impacts on cancer progression, but also uncovered a mechanism of sMIC-induced impairment of NK cell antitumor immunity. Our findings suggest that the impact of soluble NKG2D ligands should be considered in NK cellbased cancer immunotherapy and that our unique mouse models should be valuable for therapy optimization. Introduction NK cell group 2 member D (NKG2D) and its ligands are important in antitumor immunity, as evidenced in experimental animal models. NKG2D is an activating receptor expressed by all NK cells, most NKT cells, subsets of γδ T cells, all human CD8 T cells, and activated mouse CD8 T cells (1, 2). Engagement of NKG2D can activate NK cells and costimulate CD8 and γδ T cells in vitro (3-5). Enforced expression of NKG2D ligand causes tumor cells to be rejected in syngeneic mice in a manner that is dependent on NK cells and, in some cases, primed CD8 T cells (6, 7). Neutralizing NKG2D in vivo with a specific antibody enhances host sensitivity to carcinogen-induced spontaneous tumor initiation (8). NKG2D-deficient transgenic adenocarcinoma of the mouse prostate (TRAMP) mice are 3 times more likely to develop aggressive poorly differentiated (PD) prostate carcinoma than NKG2D WT TRAMP counterparts (9). Moreover, in NKG2D WT TRAMP mice, progression to PD prostate carcinoma was mostly associated with downregulation of NKG2D ligand expression by tumor cells (9).Curiously, most human tumors, in particular those of epithelial origins, express abundant NKG2D ligands yet progress to advanced diseases (10, 11), suggesting that NKG2D function is compromised in cancer patents. Various mechanisms have been proposed to explain how tumor cells evade NKG2D immunity. One prevailing concept is that exhaustion of NKG2D function

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Section: Resultsmentioning

confidence: 89%

Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

et al. 2013

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“…Although otherwise strongly responsive to the tumor Ag, it is important to note that the same antitumor T cells are poorly responsive in the tumor. As indicated by diminished T cell proliferation and cytokine production, antitumor T cells are rapidly tolerized when they move into the tumor microenvironment (46,47).…”

Section: Discussionmentioning

confidence: 99%

A2A Adenosine Receptor May Allow Expansion of T Cells Lacking Effector Functions in Extracellular Adenosine-Rich Microenvironments

Ohta

Madasu²,

Kini³

et al. 2009

The Journal of Immunology

179

136

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Immunosuppressive signaling via the A2A adenosine receptor (A2AR) provokes a mechanism that protects inflamed tissues from excessive damage by immune cells. This mechanism is desirable not only for preventing uncontrolled tissue destruction by overactive immune responses, but also for protecting tumor tissues from antitumor immune responses. In aforementioned circumstances, T cell priming may occur in an environment containing high concentrations of extracellular adenosine. To examine qualitative changes in T cells activated in the presence of adenosine, we asked whether different functional responses of T cells are equally susceptible to A2AR agonists. In this study, we demonstrate that A2AR signaling during T cell activation strongly inhibited development of cytotoxicity and cytokine-producing activity in T cells, whereas the inhibition of T cell proliferation was only marginal. Both CD8+ and CD4+ T cells proliferated well in the presence of A2AR agonists, but their IFN-γ-producing activities were susceptible to inhibition by cAMP-elevating A2AR. Importantly, the impaired effector functions were maintained in T cells even after removal of the A2AR agonist, reflecting T cell memory of the immunoregulatory effect of adenosine. Thus, although the adenosine-rich environment may allow for the expansion of T cells, the functional activation of T cells may be critically impaired. This physiological mechanism could explain the inefficiency of antitumor T cells in the tumor microenvironment.

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“…Indeed, tumor immunosuppression remains one of the major obstacles to many potentially effective cancer therapies and vaccines (3,4). Studies from mouse models of de novo tumorigenesis and clinical data from cancer patients have shown tumor-specific T cell generation and infiltration into tumor sites (4,5). Furthermore, strategies such as active immunization results in some patients having up to 30% of all their circulating CD8 þ T cells capable of reactivity to tumors (6).…”

Section: Introductionmentioning

confidence: 99%

Anti-IL-23 Monoclonal Antibody Synergizes in Combination with Targeted Therapies or IL-2 to Suppress Tumor Growth and Metastases

et al. 2011

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Immunosuppressive barricades erected by tumors during the evolution of immune escape represent a major obstacle to many potentially effective cancer therapies and vaccines. We have shown that host interleukin (IL)-23 suppresses the innate immune response during carcinogenesis and metastasis, independently of effects on the proinflammatory cytokine IL-17A. Based on these findings, we envisioned that IL-23 neutralization might offer a promising strategy to modulate immunosuppression, particularly in combination with immunostimulatory agents. Here we show that by itself a neutralizing monoclonal antibody (mAb) to IL-23 suppressed early experimental lung metastases in the B16F10 mouse model of melanoma and also modestly inhibited the subcutaneous growth of primary tumors. These antitumor effects were respectively mediated by natural killer cells or CD8 þ T cells. More notably, combinatorial treatments of anti-IL-23 mAb with IL-2 or anti-erbB2 mAb significantly inhibited subcutaneous growth of established mammary carcinomas and suppressed established experimental and spontaneous lung metastases. Overall, our results suggest the potential of anti-human IL-23 mAbs to improve the immunostimulatory effects of IL-2 and trastuzumab in the current management of some advanced human cancers. Cancer Res; 71(6); 2077-86. Ó2011 AACR.

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Rapid tolerization of virus-activated tumor-specific CD8 ⁺ T cells in prostate tumors of TRAMP mice

Cited by 64 publications

References 37 publications

Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

A2A Adenosine Receptor May Allow Expansion of T Cells Lacking Effector Functions in Extracellular Adenosine-Rich Microenvironments

Anti-IL-23 Monoclonal Antibody Synergizes in Combination with Targeted Therapies or IL-2 to Suppress Tumor Growth and Metastases

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Rapid tolerization of virus-activated tumor-specific CD8 + T cells in prostate tumors of TRAMP mice

Cited by 64 publications

References 37 publications

Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

A2A Adenosine Receptor May Allow Expansion of T Cells Lacking Effector Functions in Extracellular Adenosine-Rich Microenvironments

Anti-IL-23 Monoclonal Antibody Synergizes in Combination with Targeted Therapies or IL-2 to Suppress Tumor Growth and Metastases

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Rapid tolerization of virus-activated tumor-specific CD8 ⁺ T cells in prostate tumors of TRAMP mice