IFN-γ-Dependent Inhibition of Tumor Angiogenesis by Tumor-Infiltrating CD4+ T Cells Requires Tumor Responsiveness to IFN-γ

Beatty, Gregory L.; Paterson, Yvonne

doi:10.4049/jimmunol.166.4.2276

Cited by 179 publications

(121 citation statements)

References 52 publications

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“…Previous studies showed that activated T cells, through the release of factors, promote angiogenesis 21,22 thus facilitating tumor progression. Notwithstanding, as shown here and by previous studies, 14,15 T-cell-initiated antiangiogenic pathways can override the angiogenic effect of T-cell-derived factors. This suggests a delicate balance between T-cell-derived mediators that promote or inhibit tumor growth.…”

Section: Discussionsupporting

confidence: 79%

“…11-14 IFN-g had been implicated previously to reduce vessel formation within tumors, thus inhibiting progression of IFN-g receptor þ tumor cells. 14,15 To test for differential gene expression for IFN-g as well as angiogenic (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF)) and antiangiogenic (IP-10, MIG) factors, transcripts from cells composing the tumor mass were analyzed from 2-, 4-and 6-day-old tumors. Transcripts for MIG, IFN-g, VEGF and bFGF were detectable (Fig.…”

Section: Vaccine-induced Immune Mechanisms Affect the Blood Supply Ofmentioning

confidence: 99%

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Vaccine-induced CD8+ T cells eliminate tumors by a two-staged attack

et al. 2003

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Data presented here demonstrate that vaccine-induced CD8 þ T cells can eliminate their specific tumor-target with a two-staged attack. First, they release interferon-g that results in growth arrest of the tumor cells via induction of antiangiogenic mediators. Then, during the latter stages of the immune response, CD8 þ effector T cells eradicate the remaining tumor cells through perforinmediated lysis. A combination of these two mechanisms is highly effective in the described model, while either pathway alone fails to completely achieve tumor rejection. needed activation signals to the innate and adaptive immune system, and vaccine-induced TAAspecific CD8 þ T cells have been shown to achieve tumor rejection. 3,4 The success or failure of immune surveillance against any rapidly proliferating threat is a predicament of numbers versus time. Tumor cells grow very rapidly and can thus hold out against immune surveillance. CD8 þ Tcell-mediated lysis, the ultimate weapon to specifically eliminate transformed cells, is inefficient and time consuming, 5 potentially allowing continued expansion of a tumor even in the presence of a vigorous cytolytic T-cell response. A similar predicament is faced by antiviral CD8 þ T cells that face an even more rapidly multiplying threat. In viral systems, exemplified by a mouse model of hepatitis B virus, CD8 þ T cells can control the infection not only by lysis of virus-infected cells, but also through the release of mediators that reduced production of viral proteins, 6 required for the assembly of infectious virus.Here we demonstrate that vaccine-induced TAAspecific CD8 þ T cells can resort to a similar pathway by eliminating their specific tumor target with a twostaged attack. The model is based on an E1-deleted adenoviral vector expressing the E7 of HPV-16 (termed AdHu5E7) shown previously to induce a potent transgene product-specific CD8 þ T-cell response. 7 AdHu5E7-induced CD8 þ T cells are able to protect mice against challenge with a syngeneic tumor cell line, 4 termed TC-1, expressing the E7 and E6 oncoproteins of human papillomavirus (HPV) type-16. 8 In order to trace the vaccine-induced T cells within regressing tumors, the TC-1 cells were mixed with an extract of growth factor-reduced basement membranes called matrigel, 9 a substance that has been used extensively to study tumor angiogenesis, 10 tumor progression and cancer therapies. 11,7 Using this model, our data indicate that vaccine-induced E7-specific CD8 þ T cells invade the tumor where they initially release interferon (IFN)-g that affects growth arrest of the tumor cells. This is at least in part achieved through induction of factors, such as MIG, known to inhibit angiogeneisis, 12 which in turn is essential to permit proliferation of transformed cells within a solid tumor. At a later stage, CD8 þ effector T cells eliminate the tumor cells through cytolysis. A combination of these two mechanisms is highly effective in this experimental model, while either pathway alone ultimately fails to inhibit tumor progression....

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Section: Discussionsupporting

confidence: 79%

Section: Vaccine-induced Immune Mechanisms Affect the Blood Supply Ofmentioning

confidence: 99%

Vaccine-induced CD8+ T cells eliminate tumors by a two-staged attack

et al. 2003

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“…Overall immune responses, however, were too weak and transient to eradicate cancer cells in the majority of patients receiving immunisation (Wang, 2001). Therefore, growing attention has been paid to the value of CD4 þ T cells (Mumberg et al, 1999;Marzo et al, 2000;Beatty and Paterson, 2001;Wang, 2001) and DCs (Lespagnard et al, 1999;Almand et al, 2000) in antitumour immunity.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to CD8 þ T cells, CD4 þ T cells recognise tumour-specific antigenic peptides on MHC class II molecules via an exogenous processing pathway (Larsson et al, 2001). Cytokines, such as IL-2 or IFN-gamma, released by CD4 þ T cells upon antigenic stimulation are important for the antitumour effects of activated CD4 þ T cells in vivo (Mumberg et al, 1999;Marzo et al, 2000;Beatty and Paterson, 2001). Activation of both T-cell subsets requires the presentation of antigenic peptides on professional antigen-presenting cells (APCs) (Larsson et al, 2001).…”

mentioning

confidence: 99%

Clinical significance of immune cell infiltration within gallbladder cancer

et al. 2003

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To investigate the pathophysiological significance of infiltrating antitumour immune cells, we evaluated the quantity of immune cell intratumoral infiltration in 110 surgically resected gallbladder specimens by immunohistochemistry. We examined 45 cases of gallbladder cancer and 65 cases of benign gallbladder diseases for CD4 þ T cells, CD8 þ T cells, natural killer cells (NKCs), and dendritic cells (DCs). High levels of CD4 þ T cell, CD8 þ T cell, NKC, and DC infiltration were recognised in 51.1% (23 out of 45), 37.8% (17 out of 45), 33.3% (15 out of 45), and 48.9% (22 out of 45) of cancer specimens, respectively. High numbers of infiltrating CD4 þ and CD8 þ T cells correlated with decreasing tumour invasion, and high numbers of infiltrating DCs correlated with decreasing lymph-node tumour metastasis. Furthermore, increased infiltration of CD4 þ and CD8 þ T cells and DCs exhibited a significant correlation with prolonged survival. NKC infiltration, however, did not correlate with any of the clinicopathological factors examined. Additionally, high levels of infiltration were not identified in specimens from benign diseases, consistent with the cancerspecific activity of CD4 þ and CD8 þ T cells and DCs. In this study, we demonstrate that CD4 þ and CD8 þ tumour-infiltrating lymphocyte and DCs, but not NKCs, are important factors in the accurate prognosis of survival after surgical removal of gallbladder adenocarcinoma.

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“…Second, IFN-c produced at the tumor site can trigger production of additional inflammatory cytokines and chemokines that subsequently lead to activation and recruitment of NK cells, macrophages or granulocytes [30,31]. Third, IFNc may render tumor stroma that is essential for tumor growth vulnerable to attack by many cells of the immune system [23] and fourth, IFN-c can inhibit tumor angiogenesis [19,20,24,[32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Solid tumors “melt” from the inside after successful CD8 T cell attack

Blohm¹,

Potthoff²,

Kogel³

et al. 2006

Eur J Immunol

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Adoptive transfer of tumor-specific T cells represents a promising approach for cancer immunotherapy. Here, we visualized the anti-tumor response of CD8 T cells from P14 TCR-transgenic mice specific for the model antigen GP33 by immunohistology. P14 T cells, adoptively transferred into tumor-bearing hosts, induced regression of established 3LL-A9 GP33 and MCA102 GP33 tumors that express GP33 as a tumor-associated model antigen. Strikingly, the visible effects of P14 T cell attack, such as the destruction of the tumor vasculature and accumulation of granulocytes, were predominantly detected inside the tumor mass. In regressing tumors, P14 T cells were found in the intact rim zone but not in central areas that were infiltrated with granulocytes and lacked CD31 + endothelial cells. The rim of P14 T cell-treated tumors showed an increase in vascular density and decrease in hypoxia compared to untreated tumors. Hypoxic areas of tumors are known to exhibit decreased sensitivity to radiation therapy or chemotherapy. Thus, our data also imply that adoptive transfer of tumor-specific CD8 T cells might synergize with radiation therapy or chemotherapy in the elimination of solid tumors in vivo.

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IFN-γ-Dependent Inhibition of Tumor Angiogenesis by Tumor-Infiltrating CD4+ T Cells Requires Tumor Responsiveness to IFN-γ

Cited by 179 publications

References 52 publications

Vaccine-induced CD8+ T cells eliminate tumors by a two-staged attack

Vaccine-induced CD8+ T cells eliminate tumors by a two-staged attack

Clinical significance of immune cell infiltration within gallbladder cancer

Solid tumors “melt” from the inside after successful CD8 T cell attack

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