Targeting TNF-α to Neoangiogenic Vessels Enhances Lymphocyte Infiltration in Tumors and Increases the Therapeutic Potential of Immunotherapy

Calcinotto, Arianna; Grioni, Matteo; Jachetti, Elena; Curnis, Flavio; Mondino, Anna; Parmiani, Giorgio; Corti, Angelo; Bellone, Matteo

doi:10.4049/jimmunol.1101877

Cited by 129 publications

(122 citation statements)

References 44 publications

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“…In support of this hypothesis, we found that TRAMP mice receiving a DLI from a male-sensitized female donor experienced accelerated CD3 þ cell infiltration of the prostatic tissue (unpublished data). Thus, it is likely that the use of primed T cells, or of other strategies favoring tumor infiltration (36) and/or tumor antigen cross-presentation, might mimic the effect of tumor-directed vaccination.…”

Section: Discussionmentioning

confidence: 99%

Vaccine-Instructed Intratumoral IFN-γ Enables Regression of Autochthonous Mouse Prostate Cancer in Allogeneic T-Cell Transplantation

et al. 2013

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Vaccination can synergize with transplantation of allogeneic hematopoietic stem cells to cure hematologic malignancies, but the basis for this synergy is not understood to the degree where such approaches could be effective for treating solid tumors. We investigated this issue in a transgenic mouse model of prostate cancer treated by transplantation of a nonmyeloablative MHC-matched, single Y chromosome-encoded, or multiple minor histocompatibility antigen-mismatched hematopoietic cell preparation. Here, we report that tumordirected vaccination after allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion is essential for acute graft versus tumor responses, tumor regression, and prolonged survival. Vaccination proved essential for generation of CD8 þ IFN-g þ tumor-directed effector cells in secondary lymphoid organs and also for IFN-g þ upregulation at the tumor site, which in turn instructed local expression of proinflammatory chemokines and intratumoral recruitment of donor-derived T cells for disease regression. Omitting vaccination, transplanting IFN-g-deficient donor T cells, or depleting alloreactive T cells all compromised intratumoral IFN-g-driven inflammation and lymphocyte infiltration, abolishing antitumor responses and therapeutic efficacy of the combined approach. Our findings argue that posttransplant tumor-directed vaccination is critical to effectively direct donor T cells to the tumor site in cooperation with allogeneic hematopoietic cell transplantation. Cancer Res; 4641-52. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Vaccine-Instructed Intratumoral IFN-γ Enables Regression of Autochthonous Mouse Prostate Cancer in Allogeneic T-Cell Transplantation

et al. 2013

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“…In particular, targeting TNF to neoangiogenic vasculature, induces upregulation of ICAM-1/VCAM-2 leukocyte adhesion molecules on endothelial cells, and release of proinflammatory cytokines and chemokines in the tumor microenvironment. Remarkably, these modifications favor a rapid and long lasting infiltration of tumor-specific CD8 C T cells 11 Similarly, tumor infiltration by CD8 C T cells, was induced by an RGR-targeted TNF (i.e. TNF-RGR administered at doses in the microgram range).…”

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confidence: 99%

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

et al. 2015

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NGR-TNF is a vascular targeting agent in advanced clinical development, coupling tumor necrosis factor-a (TNF) with the CNGRCG peptide, which targets a CD13 isoform specifically expressed by angiogenic vessels. Antitumor efficacy of NGR-TNF has been described in different transplantation tumor models. Nevertheless, the mechanism underlying its activity is not fully understood. In the wild type and in the immunodeficient (RAG ¡/¡ ) RIP1-Tag2 models of multistage pancreatic carcinogenesis, we demonstrate that CD13 is highly expressed on endothelial cells of hyperplastic and angiogenic islets, whereas its expression is down regulated in tumors where it partially colocalize with pericytes. In vivo CNGRCG peptides coupled to fluorescent nanoparticles (quantum dots) bind to CD13 and colocalize with anti-CD31, in pancreatic islets. At early stage, low doses of NGR-murine (m)TNF have a direct cytotoxic effect inducing endothelial cell apoptosis, reducing vessel density and eventually inhibiting the development of angiogenic islets. At a later stage, NGRmTNF is able to reduce tumor growth inducing vascular normalization, exclusively when treatment is carried out in the immunocompetent mice. Interestingly, NGR-mTNF-treated tumors from these mice are characterized by CD8 C T cell infiltration. At molecular level, overexpression of genes involved in vessels normalization was detected only in NGRmTNF-treated tumors from immunocompetent mice.These findings identified a new mechanism of action of NGR-mTNF, providing support for the development of new therapeutic strategies combining chemotherapy or active/adoptive immunotherapies to low dose NGR-TNF treatment.

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“…Tumor necrosis factor (TNF)-α is an inflammatory cytokine frequently present in the tumor microenvironment. TNF-α is primarily secreted by tumor-associated macrophages and it initiates chronic inflammation (2). TNF-α has biphasic effects, by which it induces tumor cell apoptosis at high doses while it accelerates tumor invasion and metastasis with long-term administration of low doses (3).…”

Section: Introductionmentioning

confidence: 99%

TNF-α promotes colon cancer cell migration and invasion by upregulating TROP-2

Zhao

Zhang

2018

Oncol Lett

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Abstract. High levels of tumor-associated calcium signal transduction protein (TROP)-2 have been demonstrated to be strongly associated with tumor necrosis factor (TNF)-α levels in colon cancer. In the present study, the effect of TNF-α on the regulation of TROP-2 expression and its effect in colon cancer cell migration and invasion were investigated in vitro. TROP-2 protein levels were evaluated in HCT-116 human colon cancer cells cultured with various concentrations of TNF-α using western blot analysis. Changes in the migratory and invasive potential of the cells were evaluated using a wound healing and transwell assay, respectively. Then, TROP-2 expression was downregulated in cells by use of siRNA, and TROP-2 knockdown was confirmed at the mRNA and protein level by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The migration and invasion potential of cells transfected with TROP-2 siRNA was also evaluated. Levels of several mitogen-activated protein kinase proteins, namely p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), were detected in cells treated with TNF-α using western blot analysis. The results demonstrated that TROP-2 protein levels increased in cells treated with lower concentrations of TNF-α, but decreased in cells treated with higher concentrations of TNF-α, compared with untreated control. Maximum TROP-2 levels were observed in cells treated with 20 µg/l TNF-α. Migration and invasion were enhanced in cells treated with 20 µg/l TNF-α. When TROP-2 was silenced in colon cancer cells by siRNA, migration and invasion were significantly decreased compared with control cells. TNF-α stimulation activated the ERK1/2 pathway, but did not significantly affect p38 and JNK phosphorylation levels. Treatment with a specific ERK1/2 inhibitor suppressed the TNF-α-induced upregulation of TROP-2 and the TNF-α-induced colon cancer cell migration and invasion. In conclusion, the present results demonstrated that low concentrations of TNF-α significantly enhanced colon cancer cell migration and invasion by upregulating TROP-2 via the ERK1/2 signaling pathway. IntroductionColon cancer is a common malignant tumor of the digestive tract, from which morbidity and mortality have been increasing in recent years. Tumor invasion and metastasis are the main causes of colon cancer-associated death, but the precise mechanism mediating these processes remains unclear. Previous studies have primarily focused on the characteristics of cancer cells; however, the effects of the tumor microenvironment on invasion and metastasis have increasingly been gaining attention in recent years (1).The tumor microenvironment has an important role in tumorigenesis and disease progression. Tumor necrosis factor (TNF)-α is an inflammatory cytokine frequently present in the tumor microenvironment. TNF-α is primarily secreted by tumor-associated macrophages and it initiates chronic inflammation (2). TNF-α has biphasic effects, by which it induces tumor cell apoptosis...

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Targeting TNF-α to Neoangiogenic Vessels Enhances Lymphocyte Infiltration in Tumors and Increases the Therapeutic Potential of Immunotherapy

Cited by 129 publications

References 44 publications

Vaccine-Instructed Intratumoral IFN-γ Enables Regression of Autochthonous Mouse Prostate Cancer in Allogeneic T-Cell Transplantation

Vaccine-Instructed Intratumoral IFN-γ Enables Regression of Autochthonous Mouse Prostate Cancer in Allogeneic T-Cell Transplantation

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

TNF-α promotes colon cancer cell migration and invasion by upregulating TROP-2

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