Induction of complement attack on human cells by Gal(alpha1,3)Gal xenoantigen expression as a gene therapy approach to cancer

Jäger, Ute; Takeuchi, Yasuhiro; Porter, Colin D.

doi:10.1038/sj.gt.3300934

Cited by 16 publications

(14 citation statements)

References 31 publications

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“…A similar selection of a-gal-positive tumor cells, after transfection with a retrovirus containing the a1,3GT gene, also requires the proliferation of the transfected cells for insertion of the gene into the genome of the cell, as previously demonstrated with human cell lines processed to express this epitope. [60][61][62][63] In contrast, transduction with AdaGT results in a-gal epitope expression in a large proportion of the tumor cells (Fig 2). Therefore, in vitro transduction with AdaGT is likely to be suitable for inducing expression of a-gal epitopes on freshly obtained tumor cells that are processed as autologous tumor vaccine.…”

Section: In Vivo Targeting Of Vaccinating Tumor Cells L Deriy Et Almentioning

confidence: 99%

“…50,[60][61][62][63] Freshly isolated tumor cells that are to be manipulated in a clinical setting to serve as an autologous tumor vaccine expressing a-gal epitopes, are mostly cells that are nondividing in vitro. Expression of these epitopes on nondividing tumor cells may be achieved by transduction with replication defective adenovirus containing the a1,3GT gene.…”

Section: Transduction Of Bl6 Cells By Adagtmentioning

confidence: 99%

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In vivo targeting of vaccinating tumor cells to antigen-presenting cells by a gene therapy method with adenovirus containing the α1,3galactosyltransferase gene

et al. 2005

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Section: In Vivo Targeting Of Vaccinating Tumor Cells L Deriy Et Almentioning

confidence: 99%

Section: Transduction Of Bl6 Cells By Adagtmentioning

confidence: 99%

In vivo targeting of vaccinating tumor cells to antigen-presenting cells by a gene therapy method with adenovirus containing the α1,3galactosyltransferase gene

et al. 2005

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“…Jager et al (27) showed that ␣-galexpressing human fibrosarcoma cells HT1080 became sensitive to CDC after the removal of CD55 and CD59 with nonhuman phosphatidylinositol-specific phospholipase C (PI-PLC). Hellrung et al (24) modified A549 to coexpress ␣-gal epitope peptides and PI-PLC.…”

Section: Discussionmentioning

confidence: 99%

“…The ␣1,3GT cDNA has been cloned from New World monkey (19), mouse (37), and bovines (29). It has been successfully expressed in a number of human cell lines (14,24,27,53). The ␣-gal epitope increases the sensitivity of tumor cells to human complementdependent cytolysis (CDC) in cell lines of human pancreatic cancer (1), hepatocellular carcinoma (66), and breast cancer (52).…”

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confidence: 99%

CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of α-gal xenoantigen in colon tumor cells

Wang

Qin

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Y. CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of ␣-gal xenoantigen in colon tumor cells. Am J Physiol Gastrointest Liver Physiol 306: G1056-G1064, 2014. First published April 24, 2014 doi:10.1152/ajpgi.00464.2013.-Engineering cancer cells to express heterologous antigen ␣-gal and induce the destruction of tumor cells depending on the complement cascade may be a promising strategy of tumor therapy. However, the feasibility and effect of using ␣-gal to induce colorectal adenocarcinoma cell line cytolysis is not yet known. In this study, we evaluated ␣-gal expression's ability to sensitize human colorectal adenocarcinoma cell lines to complement attack in cell lines LoVo, SW620, and Ls-174T. Nearly all ␣-gal-expressing LoVo and SW620 cells were killed by normal human serum (NHS), but ␣-gal-expressing Ls-174T cells showed no significant lysis. We analyzed the expression levels of membrane-bound complement regulatory proteins (mCRPs) on the three cell lines, and their protective role in ␣-gal-mediated activation of the complement. LoVo showed no expression of any of the three proteins. CD59 was strongly expressed by SW620 and Ls-174T. CD46 and CD55 varied between the two cell lines. CD46 on SW620 was only half the intensity of CD46 on Ls-174T. Ls-174T showed a notable expression of CD55, while expression of CD55 on SW620 was not detected. The sensitivity of Ls-174T expressing ␣-gal to NHS greatly increased following the downregulation of CD46 and CD55 with short hairpin RNA (shRNA). However, there is no increase in cell killing when CD59 expression was diminished. Our findings suggest that the use of ␣-gal as antigen to induce tumor cell killing may be a potential therapeutic strategy in colon cancer and that CD55 plays a primary role in conferring resistance to lysis. ␣-gal epitope; membrane-bound complement regulatory proteins; complement-dependent cytotoxicity; colorectal carcinoma COLORECTAL CANCER is the third most commonly diagnosed cancer in males and the second in females (28, 57). Surgery is the mainstay of treatment in most cases of colon cancer. Adjuvant therapies, primarily chemotherapy and radiotherapy, have improved the survival rate and quality of life in colorectal cancer patients. However, the 5-yr survival rate remains at ϳ50%, which explains the growing interest in alternative therapies that have no serious side effects and that have the potential to eradicate residual tumors after conventional treatment. A deeper understanding of the interaction between the host immune system and malignant tumors has enabled the development of effective clinical strategies that improve immune responses against tumors. We seek to develop a therapeutic strategy that induces a specific immune response resulting in direct tumor cell killing, depending on the activation of the complement system.

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“…Based on the immunologic potential of anti‐αGal antibodies, the fundamental mechanisms of hyperacute rejection may be used to eradicate tumor whether tumoral cells express the αGal epitope or not. Retroviral‐mediated delivery of α1,3GT cDNA in human cells result in the membrane expression of αGal epitope, which provokes the complement‐dependent lysis of these cells [22–25]. It is also possible to increase the immunogenicity of autologous tumor vaccines in humans by expressing αGal epitope at the surface of tumoral cells [26–28].…”

Section: Introductionmentioning

confidence: 99%

Relationship between αGal epitope expression and decrease of tumorigenicity in pancreatic adenocarcinoma model

Aubert

Crotté

Benkoël

et al. 2005

Molecular Carcinogenesis

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The alphaGal epitope is a carbohydrate structure, Galalpha1,3Galbeta1,4GlcNAc-R, synthesized on glycoconjugates in many mammals by alpha1,3galactosyltransferase. Humans do not express this epitope and present in serum large amounts of naturally occuring antibodies, which recognize the alphaGal epitopes and participate in the hyperacute rejection of xenograft. Studies indicated that the fundamental mechanism of hyperacute rejection involving the alphaGal epitope expression can be used in cancer therapy. We have previously suggested that the alphaGal epitope expression by human pancreatic tumoral cells could decrease the tumorigenic behavior of these cells. To determine whether the expression of the alphaGal epitope can modify the tumorigenicity of pancreatic cancer cells, we used a Syrian golden hamster pancreatic adenocarcinoma experimental model. The expression of alphaGal epitopes in the Syrian golden hamster pancreatic cancer cell line HaP-T1 was obtained by selecting stable cell clones transfected with murine alpha1,3galactosyltransferase gene. The alphaGal epitope expression resulted in a delay in the tumoral development of HaP-T1 cells in vivo after allograft transplantation of Syrian golden hamsters (2.5-fold, P < 0.05) and of nude mice. This result is associated with an 100% increase in survival time of nude mice bearing tumors expressing the alphaGal epitope. Our results confirm that the cell surface expression of alphaGal epitope decreases the tumorigenic behavior of pancreatic cancer cells. This novel property may be useful for the development of cancer gene immunotherapy strategy.

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Induction of complement attack on human cells by Gal(alpha1,3)Gal xenoantigen expression as a gene therapy approach to cancer

Cited by 16 publications

References 31 publications

In vivo targeting of vaccinating tumor cells to antigen-presenting cells by a gene therapy method with adenovirus containing the α1,3galactosyltransferase gene

In vivo targeting of vaccinating tumor cells to antigen-presenting cells by a gene therapy method with adenovirus containing the α1,3galactosyltransferase gene

CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of α-gal xenoantigen in colon tumor cells

Relationship between αGal epitope expression and decrease of tumorigenicity in pancreatic adenocarcinoma model

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