Prostate Tumor Microenvironment Alters Immune Cells and Prevents Long-Term Survival in an Orthotopic Mouse Model Following flt3-Ligand/CD40-Ligand Immunotherapy

Ciavarra, Richard P.; Holterman, Daniel A.; Brown, Roy R.; Mangiotti, Patricia; Yousefieh, Nazita; Wright, George L.; Schellhammer, Paul F.; Glass, William F.; Somers, Kenneth D.

doi:10.1097/00002371-200401000-00002

Cited by 21 publications

(14 citation statements)

References 37 publications

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“…Previous studies by Troy et al (9) indicated that minimally activated tumor-infiltrating dendritic cells infiltrate the tumor mass of prostate cancer patients. In contrast, our studies and those of Ciavarra et al (27,28) suggest that the tumorinfiltrating dendritic cells have an immature phenotype. These conflicting observations may be due to analysis at different stages of tumor progression in the prostate cancer patients versus the mouse models.…”

Section: Discussioncontrasting

confidence: 91%

Altered Immunity Accompanies Disease Progression in a Mouse Model of Prostate Dysplasia

Tien

Xu²,

Helgason³

2005

Cancer Research

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Increasing evidence suggests that altered immune function accompanies, and indeed may facilitate, cancer progression. In this study, we sought to determine the nature of, and cellular mechanisms underlying, changes in immune status during disease progression in a transgenic mouse model of prostate dysplasia. Immune cells in the tumor microenvironment, as well as in the secondary lymphoid tissues, displayed altered phenotypes. Although evidence of antitumor immunity was detected, there was a paradoxical decrease in the ability of T cells to proliferate in vitro at later stages of disease progression. Detailed analysis of the draining lumbar lymph nodes revealed an increased frequency and number of CD4 + + + CD25 + + + T cells and an enhanced production of inhibitory cytokines, which correlated with impaired T-cell function. Functional studies confirmed a role for CD4 + + + CD25 + + + regulatory T cells in suppressing T-cell proliferation as well as regulating the growth of transplanted prostate tumor cells. In addition, our studies show for the first time that anti-CD25 antibody treatment reduces, but does not prevent, tumor growth in a transgenic mouse model of prostate dysplasia. Taken together, this work provides compelling evidence that prostate tumor progression is accompanied by altered immune function and, moreover, that regulatory T cells play an important role in this process. These studies thus provide the impetus for development of specific and effective strategies to deplete regulatory T cells, or suppress their function, as an alternative or adjunct strategy for reducing tumor growth. (Cancer Res 2005; 65(7): 2947-55)

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Section: Discussioncontrasting

confidence: 91%

Altered Immunity Accompanies Disease Progression in a Mouse Model of Prostate Dysplasia

Tien

Xu²,

Helgason³

2005

Cancer Research

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“…Other strategies to induce tumor immunity have also failed to mediate complete tumor rejection and have only delayed tumor growth (41,42). Recently, it was shown that orthotopically implanted TRAMPC-1P3 tumors developed an immunosuppressive microenvironment where dendritic cells failed to express costimulatory molecules and class II antigens, interfering with adequate T-cell activation (43). Given that TRAMPC-1 and TRAMPC-2 cell lines were derived from the prostate tumor of a male TRAMP mouse (44) and that the tumor growth kinetics follow the same pattern, it is possible that mSTEAP treatment at day 31 was too late to modify the tumor microenvironment, resulting in unsuccessful treatment.…”

Section: Discussionmentioning

confidence: 99%

In vivoEffects of Vaccination with Six-Transmembrane Epithelial Antigen of the Prostate: A Candidate Antigen for Treating Prostate Cancer

et al. 2007

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Immunotherapy may provide an alternative treatment for cancer patients, especially when tumors overexpress antigens that can be recognized by immune cells. The identification of markers and therapeutic targets that are up-regulated in prostate cancer has been important to design new potential treatments for prostate cancer. Among them, the recently identified six-transmembrane epithelial antigen of the prostate (STEAP) is considered attractive due to its overexpression in human prostate cancer tissues. Our study constitutes the first assessment of the in vivo effectiveness of STEAP-based vaccination in prophylactic and therapeutic mouse models. Two delivery systems, cDNA delivered by gene gun and Venezuelan equine encephalitis virus-like replicon particles (VRP), both encoding mouse STEAP (mSTEAP) and three vaccination strategies were used. Our results show that mSTEAP-based vaccination was able to induce a specific CD8 T-cell response against a newly defined mSTEAP epitope that prolonged the overall survival rate in tumor-challenged mice very significantly. This was achieved without any development of autoimmunity. Surprisingly, CD4 T cells that produced IFN;, tumor necrosis factor-A (TNF-A), and interleukin-2 (IL-2) played the main role in tumor rejection in our model as shown by using CD4-and CD8-deficient mice. In addition, the presence of high IL-12 levels in the tumor environment was associated with a favorable antitumor response. Finally, the therapeutic effect of STEAP vaccination was also assessed and induced a modest but significant delay in growth of established, 31 day old tumors. Taken together, our data suggest that vaccination against mSTEAP is a viable option to delay tumor growth. [Cancer Res 2007;67(3):1344-51]

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“…In fact, Troy et al indicate that minimally activated DC infiltrate the tumor mass of RCC and prostate cancer patients [139,140]. Other studies suggest that the tumor-infiltration DC have an immature phenotype and could induce a partial state of Tcell tolerance to the tumor cells, suggesting that alterations in DC maturation in the tumor microenvironment may prevent them from activating antigen-specific T cells [141,142]. It is well known that if antigen-presenting cells do not express costimulatory molecules CD80 or CD86, and thereby fail to provide an appropriate second signal for T cells, tolerance pr anergy may develop [143,144].…”

Section: Regulation Of Tadc Maturation and Function At The Tumor Sitementioning

confidence: 99%

Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies?

Shurin

Lokshin

Yurkovetsky

et al. 2006

Cancer Metastasis Rev

151

100

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The tumor microenvironment consists of a variable combination of tumor cells, stromal fibroblasts, endothelial cells and infiltrating leukocytes, such as macrophages, T lymphocytes, and dendritic cells. A variety of cytokines, chemokines and growth factors are produced in the local tumor environment by different cells accounting for a complex cell interaction and regulation of differentiation, activation, function and survival of multiple cell types. The interaction between cytokines, chemokines, growth factors and their receptors forms a comprehensive network at the tumor site, which is primary responsible for overall tumor progression and spreading or induction of antitumor immune responses and tumor rejection. Although the general thought is that dendritic cells are among the first cells migrating to the tumor site and recognizing tumor cells for the induction of specific antitumor immunity, the clinical relevance of dendritic cells at the site of the tumor remains a matter of debate regarding their role in the generation of successful antitumor immune responses in human cancers. While several lines of evidence suggest that intratumoral dendritic cells play an important role in antitumor immune responses, understanding the mechanisms of dendritic cell/tumor cell interaction and modulation of activity and function of different dendritic cell subtypes at the tumor site is incomplete. This review is limited to discussing the role of intratumoral cytokine network in the understanding immunobiology of tumor-associated dendritic cells, which seems to possess different regulatory functions at the tumor site.

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Prostate Tumor Microenvironment Alters Immune Cells and Prevents Long-Term Survival in an Orthotopic Mouse Model Following flt3-Ligand/CD40-Ligand Immunotherapy

Cited by 21 publications

References 37 publications

Altered Immunity Accompanies Disease Progression in a Mouse Model of Prostate Dysplasia

Altered Immunity Accompanies Disease Progression in a Mouse Model of Prostate Dysplasia

In vivoEffects of Vaccination with Six-Transmembrane Epithelial Antigen of the Prostate: A Candidate Antigen for Treating Prostate Cancer

Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies?

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