Capitalizing on the Immunogenicity of Dying Tumor Cells

Fonseca, Catia; Dranoff, Glenn

doi:10.1158/1078-0432.ccr-07-2245

Cited by 50 publications

(29 citation statements)

References 47 publications

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“…Stress-induced cancer cell death by means of apoptosis, necrosis, and autophagy occurs continually during tumour development and progression (Fonseca and Dranoff, 2008). What the ramifications of this to the tumour microenvironment is only beginning to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential

et al. 2009

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The tumour microenvironment is believed to be involved in development, growth, metastasis, and therapy resistance of many cancers. Here we show survivin, a member of the inhibitor of apoptosis protein (IAP) family, implicated in apoptosis inhibition and the regulation of mitosis in cancer cells, exists in a novel extracellular pool in tumour cells. Furthermore, we have constructed stable cell lines that provide the extracellular pool with either wild-type survivin (Surv-WT) or the previously described dominant-negative mutant survivin (Surv-T34A), which has proven pro-apoptotic effects in cancer cells but not in normal proliferating cells. Cancer cells grown in conditioned medium (CM) taken from Surv-WT cells absorbed survivin and experienced enhanced protection against genotoxic stresses. These cells also exhibited an increased replicative and metastatic potential, suggesting that survivin in the tumour microenvironment may be directly associated with malignant progression, further supporting survivin's function in tumourigenesis. Alternatively, cancer cells grown in CM taken from the Surv-T34A cells began to apoptose through a caspase-2-and caspase-9-dependent pathway that was further enhanced by the addition of other chemo-and radiotherapeutic modalities. Together our findings suggest a novel microenvironmental function for survivin in the control of cancer aggressiveness and spread, and should result in the genesis of additional cancer treatment modalities.

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Section: Discussionmentioning

confidence: 99%

Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential

et al. 2009

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“…Cell death confers immunogenic properties to tumor cells (45)(46)(47). In particular, necrotic cell death has long been regarded as immunogenic due to the release of damage-associated molecular patterns, like heat shock protein 70, high mobility group box 1 (48,49), and lipid membranes (50).…”

Section: Discussionmentioning

confidence: 99%

Anti-NeuGcGM3 Antibodies, Actively Elicited by Idiotypic Vaccination in Nonsmall Cell Lung Cancer Patients, Induce Tumor Cell Death by an Oncosis-Like Mechanism

Hernández

Rodríguez

González³

et al. 2011

The Journal of Immunology

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1E10 is a murine anti-idiotypic mAb specific for an idiotypic mAb that reacts with NeuGc-containing gangliosides, sulfatides, and Ags expressed in some human tumors. In melanoma, breast, and lung cancer patients, this anti-idiotypic Ab was able to induce a specific Ab response against N-glycolilated gangliosides, attractive targets for cancer immunotherapy as these glycolipids are not naturally expressed in humans. A clinical study with nonsmall cell lung cancer patients showed encouraging clinical benefits. Immunological studies performed in 20 of these patients suggested a correlation between the induction of Abs against NeuGcGM3 and longer survival times. The induced anti-NeuGcGM3 Abs recognized and directly killed tumor cells expressing the Ag, by a mechanism independent of complement activation. In the present work, we show that this cytotoxicity differs from apoptosis because it is temperature independent, no chromatin condensation or caspase 3 induction are detected, and the DNA fragmentation induced has a different pattern than the one characteristic for apoptosis. It is a very quick process and involves cytosqueleton reorganization. The Abs induce cellular swelling and the formation of big membrane lesions that allow the leakage of cytoplasm and the loss of the cell membrane integrity. All of these characteristics resemble a process of oncotic necrosis. To our knowledge, this is the first report of the active induction in cancer patients of NeuGcGM3-specific Abs able to induce complement independent oncotic necrosis to tumor cells. These results contribute to reinforcing the therapeutic potential of anti-idiotypic vaccines and the importance of NeuGcGM3 ganglioside as antitumor target.

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“…Its development including malignancy grade and patient prognosis is influenced not only by the mutations that suffer tumor cells, but also by the status of the immune system, which interacts with tumor microenvironment [1]. Some authors have reported that the immune system is unable to halt tumor progression and even more it is responsible of promoting tumorigenesis [2]. Innate immune cells, like dendritic cells (DC), natural killer cells, granulocytes, macrophages and monocytes are present in the normal mammary gland and play an important role participating in its development and remodeling, but they are also present in neoplastic tissues, such as breast tumors.…”

Section: Introductionmentioning

confidence: 99%

Cholinergic Actions of Autoantibodies from Breast Cancer Patients on Dendritic Cells

Lombardi¹

2015

J Clin Cell Immunol

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Autoantibodies (autoAbs) against self-proteins have been localized in tumor microenvironment exerting a complex network of interactions. We reported the presence of autoAbs in breast cancer patients, which promote tumor progression by activating muscarinic acetylcholine receptors (mAChR) in tumor cells. Cholinergic receptors are also expressed in dendritic cells (DC) and much clear evidence demonstrated a deficient functional activity of DC in cancer. Here we investigated whether autoAbs can modulate the expression of maturation markers and the production of cytokines by DC. IgG from breast cancer patients in stage I reduced the expression of HLA-DR and CD86 as well as tumor necrosis factor alpha liberation and augmented interleukin IL-12 and IL-10 levels by cholinergic activation of mature DC. The latter cytokines are also up-regulated in patients' sera, probably due to tumor influence, since the addition of breast tumor extract increased cytokine levels in immature DC reaching levels of mature DC mainly for IL-10 and IL-12. It could be assumed that autoAbs are reinforcing the tolerogenic/ immunosuppressive profile mediated by DC in breast cancer.

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Capitalizing on the Immunogenicity of Dying Tumor Cells

Cited by 50 publications

References 47 publications

Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential

Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential

Anti-NeuGcGM3 Antibodies, Actively Elicited by Idiotypic Vaccination in Nonsmall Cell Lung Cancer Patients, Induce Tumor Cell Death by an Oncosis-Like Mechanism

Cholinergic Actions of Autoantibodies from Breast Cancer Patients on Dendritic Cells

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