Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

Griffiths, Richard W.; Gilham, David E.; Dangoor, Adam; Ramani, Vijay; Clarke, Noel W.; Stern, Peter L.; Hawkins, Robert E.

doi:10.1038/sj.bjc.6602776

Cited by 66 publications

(44 citation statements)

References 37 publications

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“…Interestingly, PPIC maps to 5q23 and is involved in the degradation of the genome during apoptosis (45). TPBG is a tumor-associated antigen and is considered a potential target for the immunotherapy of cancer (46). TPBG expression is associated with poor prognosis in gastric and colorectal cancer (47,48).…”

Section: Discussionmentioning

confidence: 99%

Lenalidomide inhibits the malignant clone and up-regulates theSPARCgene mapping to the commonly deleted region in 5q− syndrome patients

Pellagatti

Jädersten

Forsblom

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

221

167

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Myelodysplastic syndromes (MDSs) are a group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis and peripheral blood cytopenias. Lenalidomide has dramatic therapeutic effects in patients with low-risk MDS and a chromosome 5q31 deletion, resulting in complete cytogenetic remission in >60% of patients. The molecular basis of this remarkable drug response is unknown. To gain insight into the molecular targets of lenalidomide we investigated its in vitro effects on growth, maturation, and global gene expression in isolated erythroblast cultures from MDS patients with del(5)(q31). Lenalidomide inhibited growth of differentiating del(5q) erythroblasts but did not affect cytogenetically normal cells. Moreover, lenalidomide significantly influenced the pattern of gene expression in del(5q) intermediate erythroblasts, with the VSIG4, PPIC, TPBG, activin A, and SPARC genes up-regulated by >2-fold in all samples and many genes involved in erythropoiesis, including HBA2, GYPA, and KLF1, down-regulated in most samples. Activin A, one of the most significant differentially expressed genes between lenalidomide-treated cells from MDS patients and healthy controls, has pleiotropic functions, including apoptosis of hematopoietic cells. Up-regulation and increased protein expression of the tumor suppressor gene SPARC is of particular interest because it is antiproliferative, antiadhesive, and antiangiogenic and is located at 5q31-q32, within the commonly deleted region in MDS 5q؊ syndrome. We conclude that lenalidomide inhibits growth of del(5q) erythroid progenitors and that the up-regulation of SPARC and activin A may underlie the potent effects of lenalidomide in MDS with del(5)(q31). SPARC may play a role in the pathogenesis of the 5q؊ syndrome.gene expression profiling ͉ myelodysplastic syndromes ͉ microarray ͉ erythropoiesis ͉ osteonectin

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Section: Discussionmentioning

confidence: 99%

Lenalidomide inhibits the malignant clone and up-regulates theSPARCgene mapping to the commonly deleted region in 5q− syndrome patients

Pellagatti

Jädersten

Forsblom

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

221

167

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“…The biological role of 5T4 remains unclear although it has been reported to facilitate tumour cell migration, chemotaxis and invasion [9][10][11]. 5T4 has been exploited as a cancer target using a number of therapeutic modalities including as a 5T4-specific Fab-superantigen conjugate [12], as a 5T4 antibody-drug conjugate [13] and expressed as a 5T4-specific scFv fused to signalling domains to form a chimeric antigen receptor that re-directs the functional activity of engineered T cells [14,15]. However, 5T4 has been most advanced as a target for vaccines.…”

Section: Introductionmentioning

confidence: 99%

Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy

Castro

Al-Muftah

Mulryan

et al. 2011

Cancer Immunol Immunother

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Effective vaccination against tumour-associated antigens (TAA) such as the 5T4 oncofoetal glycoprotein may be limited by the nature of the T cell repertoire and the influence of immunomodulatory factors in particular T regulatory cells (Treg). Here, we identified mouse 5T4-specific T cell epitopes using a 5T4 knock out (5T4KO) mouse and evaluated corresponding wild-type (WT) responses as a model to refine and improve immunogenicity. We have shown that 5T4KO mice vaccinated by replication defective adenovirus encoding mouse 5T4 (Adm5T4) generate potent 5T4-specific IFN-γ CD8 and CD4 T cell responses which mediate significant protection against 5T4 positive tumour challenge. 5T4KO CD8 but not CD4 primed T cells also produced IL-17. By contrast, Adm5T4-immunized WT mice showed no tumour protection consistent with only low avidity CD8 IFN-γ, no IL-17 T cell responses and no detectable CD4 T cell effectors producing IFN-γ or IL-17. Treatment with anti-folate receptor 4 (FR4) antibody significantly reduced the frequency of Tregs in WT mice and enhanced 5T4-specific IFN-γ but reduced IL-10 T cell responses but did not reveal IL-17-producing effectors. This altered balance of effectors by treatment with FR4 antibody after Adm5T4 vaccination provided modest protection against autologous B16m5T4 melanoma challenge. The efficacy of 5T4 and some other TAA vaccines may be limited by the combination of TAA-specific T regs, the deletion and/or alternative differentiation of CD4 T cells as well as the absence of distinct subsets of CD8 T cells.

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“…The human onco-fetal antigen, 5T4, is a 72kDa leucine-rich membrane glycoprotein which is expressed at high levels on the placenta and also on a wide range of human carcinomas including colorectal, gastric, renal and ovarian but rarely on normal tissues [13], [14], [15], [16], [17], [18]. In this study we tested the hypothesis that Treg develop in CRC patients that suppress 5T4-specific immune responses.…”

Section: Introductionmentioning

confidence: 99%

CD4+CD25+FOXP3+ Regulatory T Cells Suppress Anti-Tumor Immune Responses in Patients with Colorectal Cancer

et al. 2006

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BackgroundA wealth of evidence obtained using mouse models indicates that CD4+CD25+FOXP3+ regulatory T cells (Treg) maintain peripheral tolerance to self-antigens and also inhibit anti-tumor immune responses. To date there is limited information about CD4+ T cell responses in patients with colorectal cancer (CRC). We set out to measure T cell responses to a tumor-associated antigen and examine whether Treg impinge on those anti-tumor immune responses in CRC patients.Methodology and Principal FindingsTreg were identified and characterized as CD4+CD25+FOXP3+ using flow cytometry. An increased frequency of Treg was demonstrated in both peripheral blood and mesenteric lymph nodes of patients with colorectal cancer (CRC) compared with either healthy controls or patients with inflammatory bowel disease (IBD). Depletion of Treg from peripheral blood mononuclear cells (PBMC) of CRC patients unmasked CD4+ T cell responses, as observed by IFNγ release, to the tumor associated antigen 5T4, whereas no effect was observed in a healthy age-matched control group.Conclusions/SignificanceCollectively, these data demonstrate that Treg capable of inhibiting tumor associated antigen-specific immune responses are enriched in patients with CRC. These results support a rationale for manipulating Treg to enhance cancer immunotherapy.

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Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

Cited by 66 publications

References 37 publications

Lenalidomide inhibits the malignant clone and up-regulates theSPARCgene mapping to the commonly deleted region in 5q− syndrome patients

Lenalidomide inhibits the malignant clone and up-regulates theSPARCgene mapping to the commonly deleted region in 5q− syndrome patients

Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy

CD4+CD25+FOXP3+ Regulatory T Cells Suppress Anti-Tumor Immune Responses in Patients with Colorectal Cancer

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