Human CTLs to Wild-Type and Enhanced Epitopes of a Novel Prostate and Breast Tumor-Associated Protein, TARP, Lyse Human Breast Cancer Cells

Oh, Sang Kon; Terabe, Masaki; Pendleton, C. David; Bhattacharyya, Anu; Bera, Tapan K.; Epel, Malka; Reiter, Yoram; Phillips, John W.; Linehan, W. Marston; Kasten-Sportès, Claude; Pastan, Ira; Berzofsky, Jay A.

doi:10.1158/0008-5472.can-03-2183

Cited by 71 publications

(86 citation statements)

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“…We have previously used the scHLA-A2/TARP complexes in the form of tetramers in order to detect TARP-specific CTL from patients' PBMC [17].…”

Section: Resultsmentioning

confidence: 99%

“…For TARP 29-37, Arg at position 3 and Leu at position 9 were substituted with Ala (TARP 29-37-3A) and Val (TARP 29-37-9V), respectively. These substitutions were shown to increase the affinity of the peptide to HLA-A2 [17]. To determine the fine specificity of the D2 Fab TCR-like antibody, tests were conducted in order to assess its reactivity with the modified peptides.…”

Section: Resultsmentioning

confidence: 99%

“…It was shown that TARP was expressed on >90% of cancer specimens examined [9,15]. In order to define new breast and prostate CD8 + T cell tumor antigens, two wild-type HLA-A2 epitopes from TARP were identified [17]. The wild-type sequences were also improved by sequence modifications to produce epitopeenhanced peptides.…”

Section: Introductionmentioning

confidence: 99%

“…The refolded scHLA-A2/TARP complexes were found to be highly purified, homogenous, and monomeric by SDS-PAGE (data not shown). Recombinant scMHC-peptide complexes generated by this strategy had been previously characterized in detail for their biochemical, biophysical and biological properties, and were found to be correctly folded and functional [35,36].We have previously used the scHLA-A2/TARP complexes in the form of tetramers in order to detect TARP-specific CTL from patients' PBMC [17].To select TCR-like antibodies, we used a large naive Fab antibody phage library consisting of a repertoire of 3.7 Â 10 10 independent Fab clones [37]. In our selection strategy (see Materials and methods), we first depleted the library of streptavidin binders and subsequently applied the library to panning in solution on soluble recombinant scHLA-A2-peptide complexes containing the native TARP 29-37 peptide.…”

mentioning

confidence: 99%

“…TARP is a newly found protein expressed in breast and prostate cancers [16,55]. It was reported that human CD8 T cells from a prostate cancer patient, specific for peptides derived from TARP, kill a human breast cancer cell line [17].With the aim of mimicking this T cell specificity by generating recombinant antibodies toTARP/HLA-A2 complexes, we generated a new tool to study antigen presentation on TARP-positive tumor cells as well as on APC. We have shown that the TCR-like antibody Fab D2 can specifically bind purified TARP/HLA-A2 complexes but not other control complexes presenting tumor-or viral-derived HLA-A2-restricted peptides.…”

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confidence: 99%

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Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

et al. 2008

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MHC class I molecules are important components of immune surveillance. There are no available methods to directly visualize and determine the quantity and distribution of MHC/ peptide complexes on individual cells or to detect such complexes on antigen-presenting cells in tissues. MHC-restricted recombinant antibodies with the same specificity of T cell receptors (TCR) may become a valuable tool to address these questions. They may also serve as valuable targeting molecules that mimic the specificity of cytotoxic T cells. We isolated by phage display a panel of human recombinant Fab antibodies with peptidespecific, MHC-restricted TCR-like reactivity directed toward HLA-A2-restricted T cell epitopes derived from a novel antigen termed TCRc alternative reading frame protein (TARP) which is expressed on prostate and breast cancer cells. We have characterized one of these recombinant antibodies and demonstrated its capacity to directly detect specific HLA-A2/ TARP T cell epitopes on antigen-presenting cells that have complexes formed by naturally occurring active intracellular processing of the antigen, as well as on the surface of tumor cells. Moreover, by genetic fusion we armed the TCR-like antibody with a potent toxin and demonstrated that it can serve as a targeting moiety killing tumor cells in a peptide-specific, MHC-restricted manner similar to cytotoxic T lymphocytes. Key words: Immunotoxin Á MHC Á Recombinant antibody Á T-cell receptor IntroductionMost patients with metastatic prostate and breast cancers are provided with the limited benefits from standard chemo-and hormone-based therapies. During the recent years, much effort has been invested in developing new approaches, such as immunotherapy, to improve the therapeutic abilities, by combining the tumor specificity of cell-mediated immunity with the freedom from toxic chemotherapies.Recent immunotherapy approaches employ the principle that CD8 + CTL recognize and kill tumor cells that display peptides from tumor-associated antigens presented by MHC class I molecules. Several tumor antigens and HLA allele-specific peptides from prostate cancer-associated antigens have been identified as CD8 + T cell epitopes, including HLA-A2-binding peptides derived from prostate-specific antigen (PSA) [1,2], prostate-specific membrane antigen (PSMA) [3], prostate stem cell antigen (PSCA) [4,5], and prostate acid phosphatase 6, which are all now components of current vaccine trials [5][6][7][8][9][10][11].Identification of new tumor-specific antigens is an essential step for the successful development of immunotherapy ap- [12][13][14]. One of these, T cell receptor gamma alternate reading frame protein (TARP), is expressed on breast and prostate cancer cells [15,16]. It was shown that TARP was expressed on >90% of cancer specimens examined [9,15]. In order to define new breast and prostate CD8 + T cell tumor antigens, two wild-type HLA-A2 epitopes from TARP were identified [17]. The wild-type sequences were also improved by sequence modifications to produce epitopeenha...

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“…We have previously used the scHLA-A2/TARP complexes in the form of tetramers in order to detect TARP-specific CTL from patients' PBMC [17].…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

et al. 2008

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Spherical Nucleic Acid Vaccine Structure Markedly Influences Adaptive Immune Responses of Clinically Utilized Prostate Cancer Targets

Teplensky

Dittmar

Qin

et al. 2021

Adv Healthcare Materials

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Cancer vaccines, which activate the immune system against a target antigen, are attractive for prostate cancer, where multiple upregulated protein targets are identified. However, many clinical trials implementing peptides targeting these proteins have yielded suboptimal results. Using spherical nucleic acids (SNAs), we explore how precise architectural control of vaccine components can activate a robust antigen-specific immune response in comparison to clinical formulations of the same targets. The SNA vaccines incorporate peptides for human prostate-specific membrane antigen (PSMA) or T-cell receptor 𝜸 alternate reading frame protein (TARP) into an optimized architecture, resulting in high rates of immune activation and cytolytic ability in humanized mice and human peripheral blood mononuclear cells (hPBMCs). Specifically, administered SNAs elevate the production and secretion of cytokines and increase polyfunctional cytotoxic T cells and effector memory. Importantly, T cells raised from immunized mice potently kill targets, including clinically relevant cells expressing the whole PSMA protein. Treatment of hPBMCs increases costimulatory markers and cytolytically active T cells. This work demonstrates the importance of vaccine structure and its ability to reformulate and elevate clinical targets. Moreover, it encourages the field to reinvestigate ineffective peptide targets and repackage them into optimally structured vaccines to harness antigen potency and enhance clinical outcomes.

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Role of CD4 T cell helper subsets in immune response and deviation of CD8 T cells in mice*

et al. 2017

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The ability of different CD4+ T cell subsets to help a CD8+ T cell response is not fully understood. Here, we found that Th17 cells induced by IL-1β, unlike Th1, were not effective helpers for antiviral CD8 responses as measured by IFNγ-producing cells or protection against virus infection. However, they skewed CD8 responses to a Tc17 phenotype. Thus, the apparent lack of help was actually immune deviation. This skewing depended on both IL-21 and IL-23. To overcome this effect, we inhibited Th17 induction by blocking TGF-β. Anti-TGF-β allowed the IL-1β adjuvant to enhance CD8+ T cell responses without skewing the phenotype to Tc17, thereby providing an approach to harness the benefit of common IL-1-inducing adjuvants like alum without immune deviation.

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Human CTLs to Wild-Type and Enhanced Epitopes of a Novel Prostate and Breast Tumor-Associated Protein, TARP, Lyse Human Breast Cancer Cells

Cited by 71 publications

References 48 publications

Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

Spherical Nucleic Acid Vaccine Structure Markedly Influences Adaptive Immune Responses of Clinically Utilized Prostate Cancer Targets

Role of CD4 T cell helper subsets in immune response and deviation of CD8 T cells in mice*

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