Specific Targeting of a Naturally Presented Osteosarcoma Antigen, Papillomavirus Binding Factor Peptide, Using an Artificial Monoclonal Antibody

Tsukahara, Tomohide; Emori, Makoto; Murata, Kenji; Hirano, Takahisa; Muroi, Norihiro; Kyono, Masanori; Toji, Shingo; Watanabe, Kazue; Torigoe, Toshihiko; Kochin, Vitaly; Asanuma, Hiroko; Matsumiya, Hiroshi; Yamashita, Keiji; Himi, Tetsuo; Ichimiya, Shingo; Wada, Takuro; Yamashita, Toshihiko; Hasegawa, Tadashi; Sato, Noriyuki

doi:10.1074/jbc.m114.568725

Cited by 10 publications

(16 citation statements)

References 37 publications

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“…Targeting ZNF395 or its downstream effectors in future studies may be therapeutically relevant to both ccRCC and other hypoxic solid malignancies. Direct targeting of ZNF395 using a peptidebased cancer vaccine is undergoing phase I trials in patients with sarcoma (107)(108)(109), opening up the possibility of using immunotherapy to target the extracellular fragments of nuclear master regulators. Our study suggests that initiating a similar trial in ccRCC may be worthwhile.…”

Section: Discussionmentioning

confidence: 99%

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

et al. 2017

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Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau ( VHL ) tumor suppressor. Roles for noncoding cis -regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profi les, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specifi c aspects of malignancy. Superenhancer profi ling identifi ed ZNF395 as a ccRCCspecifi c and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo . VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specifi c driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGnIFICAnCE:Comprehensive epigenomic profi ling of ccRCC establishes a compendium of somatically altered cis -regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL , a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specifi c promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305.

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Section: Discussionmentioning

confidence: 99%

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

et al. 2017

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“…Antitumor responses are modulated by the recognition of immunogenic epitopes in the context of human leukocyte antigen (HLA) class I in the tumors (21). Therefore, it is important to evaluate the infiltrations of immune cells and the presence of HLA class I in the tumors.…”

Section: Introductionmentioning

confidence: 99%

Frequent expression of human leukocyte antigen class I and the status of intratumoral immune cells in alveolar soft part sarcoma

et al. 2017

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The prognosis of alveolar soft part sarcoma is poor, despite the slow growth of the tumor. A number of cases with spontaneous regression of this rare tumor have been reported. Although the mechanisms underlying spontaneous regression remain uncertain, local immune reaction may be a possible contributing factor. Immunohistochemical expression of human leukocyte antigen (HLA) class I, cluster of differentiation (CD) 3, CD4, CD8, CD20, CD45, CD56, CD68, CD138 and CD163 were assessed in a series of 10 alveolar soft part sarcomas, and the expression profiles were associated with patients' clinicopathological parameters. Expression of HLA class I was observed in almost all the tumor cells of all cases. CD8(+) cells were identified in all tumors with varying densities. Moderate infiltration of CD8(+) cells was detected in three patients; one of these patients survived with long-term tumor remission. Infiltration of CD10(+), CD20(+), CD56(+) or CD138(+) cells was not revealed in all tumors. Moderate-diffuse infiltration of CD163(+) cells was observed in all tumors. To the best of our knowledge, the present study represents the first report of intratumoral immune cells in alveolar soft part sarcoma. Frequent expression of HLA class I in tumor cells was observed. CD8(+) cells were identified at various densities and CD163(+) cells were observed in alveolar soft part sarcoma. Moderate infiltration of CD8(+) cells in patients with a good prognosis may indicate the antitumor effects of immune cells in alveolar soft part sarcoma.

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“…Although combination therapy using peptide vaccination and immune checkpoint inhibitors might be a possible option, we think that the antibody therapy targeting HLA class I/antigenic peptide complexes specifically expressed on tumor cells might also be attractive. We constructed on scFv (single chain variable fragment) phage display library and successfully isolated the scFv clone recognizing the HLA‐A2/PBF‐derived peptide complex on osteosarcoma cells . Now we are developing an scFv directed at the HLA‐A24/peptide encoded by CSC antigen DNAJB8, which are expressed in the nuclei of CSCs/CICs but not in normal organs except for the testis, which lacks HLA class I molecules (Fig.…”

Section: Future Perspectives: Peptide Vaccination Therapy Targeting Cmentioning

confidence: 99%

Peptide vaccination therapy: Towards the next generation

Tsukahara

Hirohashi

Kanaseki

et al. 2016

Pathology International

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The aim of peptide vaccination therapy is to stimulate and activate peptide-specific T cells to reject tumor cells. This strategy has been promoted by the discovery of tumorassociated antigens recognized by T cells. Peptide vaccination therapy can induce immune responses in some cancer patients but the objective clinical response rates are still low. To improve of the efficacy of peptide vaccination therapy: (i) cancer stem cell antigens specifically expressed in carcinoma/sarcoma stem-like cells but not in normal cells are needed; (ii) peptide vaccination therapy should be performed in the earlier stages; and (iii) memory T stem cells should be regulated to maintain long-lasting immune responses to the peptide vaccination.

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Specific Targeting of a Naturally Presented Osteosarcoma Antigen, Papillomavirus Binding Factor Peptide, Using an Artificial Monoclonal Antibody

Cited by 10 publications

References 37 publications

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

Frequent expression of human leukocyte antigen class I and the status of intratumoral immune cells in alveolar soft part sarcoma

Peptide vaccination therapy: Towards the next generation

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