Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression

Melcher, Alan; Todryk, Stephen; Hardwick, Nicola; Ford, M. J.; Jacobson, Marcus; Vile, Richard G.

doi:10.1038/nm0598-581

Cited by 407 publications

(313 citation statements)

References 33 publications

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“…These modalities induce tumour cell necrosis, and an inflammatory microenvironment, which is critical for eliciting an efficient immune response (Melcher et al, 1998;Todryk et al, 1999;Sauter et al, 2000). Cell death following irradiation, 'conventional' chemotherapy and conventional hyperthermia (p42.51C) is mainly apoptotic (Cummings et al, 1997), which should give a less immunogenic response.…”

Section: Discussionmentioning

confidence: 99%

Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response

et al. 2005

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Previous studies in our laboratory have shown that interstitial laser thermotherapy (ILT) of an experimental liver tumour is superior to surgical excision, at least partly due to a laser-induced immunological effect. The aim of the present study was to investigate the time -response relationship of the ILT-induced immunisation and the cellular response of macrophages and lymphocytes. A dimethylhydrazine-induced adenocarcinoma was transplanted into the liver of syngeneic rats. Rats with tumour were treated 6 -8 days later (tumour size 0.25 -0.40 cm 3 ) with ILT of tumour or resection of the tumour-bearing lobe. Two groups of rats without tumour were treated with resection of a normal liver lobe or ILT of normal liver. A challenging tumour was implanted into the liver of each rat 2, 5 or 10 weeks after primary treatment. Rats were killed 6, 12 and 48 days (or earlier due to their condition) after challenge (n ¼ 8 in all groups). Immunohistochemical techniques were used to determine lymphocytes (CD8, CD4) and macrophages (ED1, ED2) in rats having had treatment of a primary tumour. Interstitial laser thermotherapy of the first tumour was followed by eradication of challenging tumour and absence of tumour spread. This contrasted with rapid growth and spread of challenging tumour in the other groups. In the challenging vital tumour tissue and in the interface between the tumour and surroundings, the number of ED1 macrophages and CD8 lymphocytes was higher in rats having been treated with the ILT of tumour than in those having undergone resection of the tumour-bearing lobe. The number of ED2 macrophages and CD4 lymphocytes was low and did not vary between these two groups. Interstitial laser thermotherapy elicited an immune response that eradicated a challenging tumour and was associated with increased numbers of tumour-infiltrating macrophages and CD8 lymphocytes.

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Section: Discussionmentioning

confidence: 99%

Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response

et al. 2005

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“…Cell death induced by tk can occur via apoptotic-independent 11,16 or dependent routes 5,16 and the latter pathway may not require p53. 17,18 Therefore tk/GCV treatment may also be applicable in therapy of p53-mutated tumours.…”

Section: Discussionmentioning

confidence: 99%

Intercellular delivery of thymidine kinase prodrug activating enzyme by the herpes simplex virus protein, VP22

et al. 1999

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We demonstrate that fusion proteins consisting of the her-COS cells transfected with tk alone. Tumours established pes simplex virus (HSV) transport protein VP22 linked in in mice with neuroblastoma cell lines expressing VP22-tk frame to HSV thymidine kinase (tk) retain the ability to be regressed upon administration of ganciclovir. Furthermore transported between cells. In vivo radiolabelling experitumours established from 50:50 mixtures of VP22-tk transments and in vitro assays show that the fusion proteins duced and nontransduced cells also regressed while no also retain tk activity. When transfected COS cells, acting significant effect was observed in similar experiments with as a source of the VP22-tk chimera, were co-plated on to cells transduced with tk alone. VP22 mediated transport gap junction-negative neuroblastoma cells, ganciclovir may thus have application in a clinical setting to amplify treatment induced efficient cell death in the recipient neurodelivery of the target protein in enzyme-prodrug protocols. blastoma cell monolayer. No such effect was observed with

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“…45 Within a given tumor cell type, the tumor cell may proceed by default along the apoptotic pathway but may switch to a nonapoptotic pathway if apoptosis is blocked, e.g., by Bcl -2 overexpression. 34 Apoptosis can start from two different pathways -the death receptor pathway and the mitochondrial pathwaywith both pathways eventually converging to activate effector caspases. 1,37,44,49 TK / GCV -induced apoptosis in SH -EP neuroblastoma cells is triggered by ligand -independent aggregation of CD95, which recruits the adaptor molecule FADD and caspase -8, forming a death -inducing signaling complex ( DISC ).…”

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confidence: 99%

TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

et al. 2002

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The clinical benefit of suicide gene therapy of tumors has been marginal, mostly due to the low gene transfer efficiency in vivo. The death -inducing ligand, TRAIL, effectively kills many tumor cell types, while sparing most normal tissues. We hypothesized that TRAIL may enhance HSV thymidine kinase / ganciclovir ( TK / GCV ) gene therapy of tumor cells by augmenting both target and bystander cell kill. Human SH -EP neuroblastoma cells expressing TK as well as bystander cells were effectively killed by apoptosis, and their clonogenicity was ablated following GCV. Human TRAIL enhanced TK / GCV -induced cell death and decreased clonogenicity of TK -expressing cells and also of bystander cells. Cooperation between TRAIL and TK / GCV depended both on caspase activation and on mitochondrial apoptogenic function because both the broad -spectrum caspase inhibitor zVAD.fmk and overexpression of Bcl -2 decreased enhancement of cell kill by TRAIL. Facilitation of TRAIL signalling by up -regulation of TRAIL receptors did not contribute to enhancement because cell surface expression of the agonistic TRAIL receptors 1 and 2 was not increased by TK / GCV. In conclusion, the concerted activation of caspases and the mitochondrial amplification of caspase activation by TK / GCV may explain the cooperative effect of TK / GCV and TRAIL on the kill of neuroblastoma cells. Because combined treatment also augmented the bystander cell kill, the addition of TRAIL may increase the efficacy of TK / GCV gene therapy of neuroblastoma.

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Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression

Cited by 407 publications

References 33 publications

Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response

Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response

Intercellular delivery of thymidine kinase prodrug activating enzyme by the herpes simplex virus protein, VP22

TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

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