Effect of CD4+CD25+ and CD4+CD25− T Regulatory Cells on the Generation of Cytolytic T Cell Response to a Self but Human Tumor-Associated Epitope In Vitro

Chattopadhyay, Subhasis; Mehrotra, Shikhar; Chhabra, Arvind; Hegde, Upendra P.; Mukherji, Bijay; Chakraborty, Nitya G.

doi:10.4049/jimmunol.176.2.984

Cited by 47 publications

(68 citation statements)

References 55 publications

(69 reference statements)

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“…4). Many previous studies have demonstrated the inhibition of tumor-specific CTL function by T regulatory cells [45,46]. In our studies, Survivin did not significantly alter Treg numbers or function (Supplementary Figure 5).…”

Section: Discussionsupporting

confidence: 59%

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

Jutzy

Khan

Asuncion-Valenzuela

et al. 2012

Cancer Microenvironment

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Clinical studies of T cell profiles from cancer patients have shown a skewing toward a type-2 T cell response with decreased cytotoxic T cell function. However, the primary cause of this shift remains unknown. Here we show that tumor-released Survivin, an inhibitor of apoptosis (IAP) protein and tumor-specific antigen, is taken up by T cells and alters their response. The addition of Survivin to T cell cultures resulted in decreased T cell proliferation and reduced cytotoxic CD8 + T cell function. Additionally, type 1 cell numbers and IFN-γ and IL-2 production were significantly reduced, while IL-4 release and type 2 T cell numbers increased. In contrast, the function and numbers of Th17 and T regulatory cells were not affected. These studies show that tumor-released Survivin modulates T cells resulting in a phenotype similar to that observed in cancer patients with a polarity shift from a type 1 to a type 2 response.

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Section: Discussionsupporting

confidence: 59%

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

Jutzy

Khan

Asuncion-Valenzuela

et al. 2012

Cancer Microenvironment

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“…135 Furthermore, although these studies have primarily focused on CD25 1 nTregs, it is likely that other Treg populations, such as Tr1 and Th3, also play a role in the suppression of immunity to tumours. 136,137 Depletion of Tregs may provide an effective means of improving the clinical effect of NY-ESO-1-based vaccines. Approaches include the use of low-dose cyclophosphamide 138 and ONTAK, a fusion toxin that targets cells via CD25.…”

Section: Approaches To Remove/inhibit Regulatory T Lymphocytes (Tregs)mentioning

confidence: 99%

Directions in the immune targeting of cancer: Lessons learned from the cancer‐testis Ag NY‐ESO‐1

et al. 2006

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Summary Since the early 1990s, numerous cancer Ag have been defined and for a handful of these there is now some clinical experience, which has made it possible to assess their value as targets for cancer immunotherapy. The cancer-testis Ag have been particularly attractive because their expression is limited to cancer and virtually no nonmalignant cells apart from germ cells and trophoblast. Among these, NY-ESO-1 has been the focus of our attention. The exceptional immunogenicity of this Ag coupled with its widespread distribution among many cancer types make it a very good vaccine candidate, with the potential to be used in vaccines against many types of malignancies. This article reviews emerging knowledge about the biology of NY-ESO-1 and experience with the early clinical development of vaccines directed against NY-ESO-1. These early studies have yielded a wealth of information about the immunology of NY-ESO-1 and set the scene for future clinical strategies for immune targeting of cancer.Key words: cancer immunology, cancer-testis Ag, cancer vaccine, dendritic cell, ISCOMATRIX, NY-ESO-1. Biology of NY-ESO-1NY-ESO-1 was first discovered using 'SERological identification of antigens by recombinant EXpression cloning' (SEREX). This is a method used for identifying the antibody repertoire of cancer-bearing patients by screening their serum against an expression library that typically displays protein Ag derived from a cancer source such as an autologous tumour or a cell line. In this case, NY-ESO-1 was found by using serum from a patient with squamous cell carcinoma (SCC) of the oesophagus. 1,2 Expression of NY-ESO-1 protein has been shown in multiple cancer types (Table 1), as well as in spermatogonia, oogonia and placenta. 3,4 Although NY-ESO-1 mRNA expression has been detected at low levels in some other normal tissues, it is unclear whether this is significant in the absence of detectable protein. 4,5 Other genes with similar names (NY-ESO-2, -3, -4, -5, -6, -7, -8) have no homology with NY-ESO-1. 2 The NY-ESO-1 gene is located on chromosome Xq28, 1 which carries a disproportionately high number of cancertestis (CT) Ag genes. 6 Up to 10% of the genes on chromosome X are CT Ag genes. The expression of these genes seems to be related to the demethylation of the promoter regions because experimental demethylation leads to the upregulation of CT Ag expression. [7][8][9][10][11][12][13][14][15][16][17][18] The NY-ESO-1 gene encodes a protein of 180 amino acids with M r 18 kDa, 2 which is expressed primarily in the cytoplasm although nuclear expression can be seen in some spermatogonia. 4 A homologue of NY-ESO-1, termed LAGE-1, was identified using representational difference analysis. 14 LAGE-1 and NY-ESO-1 are 84-89% homologous at the protein level. 14 Alternative splicing of LAGE-1 mRNA leads to the expression of two major transcripts encoding proteins of 210 and 180 amino acids, respectively. LAGE-1 is expressed in a wide variety of cancers (Table 1), usually, but not always, in conjunction with NY-ESO-1 or ...

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“…For example, it has recently been shown that generation of antigen specific CD8 T cells failed in the presence of CD4 T cells. 52 This is the result of induction of T regulatory cells, which can significantly inhibit antigen specific MART-1 CTL induction. 52 It is interesting that significant 5T4 responses of CD4 T cell enriched populations are most apparent with depletion of the CD25 1 T cells (Elkord et al, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…52 This is the result of induction of T regulatory cells, which can significantly inhibit antigen specific MART-1 CTL induction. 52 It is interesting that significant 5T4 responses of CD4 T cell enriched populations are most apparent with depletion of the CD25 1 T cells (Elkord et al, unpublished data). This observation implies that the availability of the 5T4 repertoire of both CD4 and CD8 T cells may be optimally accessed in the absence of T regulatory activity.…”

Section: Discussionmentioning

confidence: 99%

Cd8 T‐cell recognition of human 5T4 oncofetal antigen

Smyth

Elkord

Taher

et al. 2006

Intl Journal of Cancer

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The 5T4 oncofetal antigen is expressed by a wide variety of human carcinomas, including colorectal, ovarian and gastric carcinomas. The restricted expression of 5T4 on tumor tissues as well as its implication in tumor progression and bad prognosis makes 5T4 a promising new candidate for immunotherapy. An MVA vaccine encoding 5T4 antigen has been successfully evaluated in preclinical studies in a murine tumor model. Here, we report the generation of human CD8 T cells specific for the 5T4 antigen by stimulation with autologous monocyte derived DC infected with a replication defective adenovirus encoding the 5T4 cDNA (Ad5T4). Analysis of several donors confirms a repertoire of such CD8 responses. In a parallel approach, incorporating the results of proteasome-mediated digestion of 5T4 derived 35-mer peptides and the potential high affinity epitopes predicted by a computer-based algorithm, we identified 8 putative HLA-A*0201-presented CD8 MHC class I epitopes of 5T4 antigen. Two of these generated specific CD8 T cells after restimulation with peptide loaded autologous DC and assay by cytotoxicity and IFNc ELISPOT. Moreover these particular peptide generated T cells recognized naturally 5T4 positive tumor cells only if they expressed HLA-A*0201 as judged by IFNc ELISPOT or ELISA. Also, HLA-A*0201 CD8 T cells recognized these peptides in a DC-Ad5T4 polyclonal response. In conclusion, there is a repertoire of CD8 T cell recognition of 5T4 in normal human donors and some candidate HLA-A*0201 epitopes have been identified. ' 2006 Wiley-Liss, Inc.Key words: 5T4 oncofetal antigen; dendritic cells; adenovirus; proteasome; CD8 T cells There are several types of human tumor-associated antigens (TAAs), which are being exploited as targets for developing immunotherapies against malignant tumors. 1-4 Such antigens include, over or selectively expressed normal molecules (differentiation, oncofetal antigens), viral-and tumor-specific antigens, including mutated products (sometimes functional in the transformed state). Human 5T4 is a 72 kDa cell surface oncofetal antigen defined by a monoclonal antibody raised against wheat germ agglutinin-glycoproteins isolated from human syncytiotrophoblast microvillus plasma membranes. 5,6 The 5T4 antigen is highly expressed in trophoblast, but shows relatively limited expression in other normal tissues. 7 In contrast, the 5T4 antigen is upregulated in a wide variety of human carcinomas, including colorectal, gastric and ovarian carcinomas, where it is associated with poor clinical outcome. [8][9][10][11][12] The restricted expression of 5T4 antigen on tumor tissues as well as its association with tumor progression makes it a promising new candidate for immunotherapy. Several approaches to developing immunotherapies against this target are under development. Thus, we are harnessing the tumor cell surface expression of 5T4, by using antibodies to targeted drugs and/ or activation of effectors 13,14 or retargeting using chimeric immune receptors of polyclonal T-cell populations. 15,16 Our work in...

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Effect of CD4+CD25+ and CD4+CD25− T Regulatory Cells on the Generation of Cytolytic T Cell Response to a Self but Human Tumor-Associated Epitope In Vitro

Cited by 47 publications

References 55 publications

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

Directions in the immune targeting of cancer: Lessons learned from the cancer‐testis Ag NY‐ESO‐1

Cd8 T‐cell recognition of human 5T4 oncofetal antigen

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