Identification of Novel HLA-A*24:02-Restricted Epitope Derived from a Homeobox Protein Expressed in Hematological Malignancies

The homeobox protein, PEPP2 (RHOXF2), has been suggested as a cancer/testis (CT) antigen based on its expression pattern. However, the peptide epitope of PEPP2 that is recognized by cytotoxic T cells (CTLs) is unknown. In this study, we revealed that PEPP2 gene was highly expressed in myeloid leukemia cells and some other hematological malignancies. This gene was also expressed in leukemic stem-like cells. We next identified the first reported epitope peptide (PEPP2271-279). The CTLs induced by PEPP2271-279 recognized PEPP2-positive target cells in an HLA-A*24:02-restricted manner. We also found that a demethylating agent, 5-aza-2’-deoxycytidine, could enhance PEPP2 expression in leukemia cells but not in blood mononuclear cells from healthy donors. The cytotoxic activity of anti-PEPP2 CTL against leukemic cells treated with 5-aza-2’-deoxycytidine was higher than that directed against untreated cells. These results suggest a clinical rationale that combined treatment with this novel antigen-specific immunotherapy together with demethylating agents might be effective in therapy-resistant myeloid leukemia patients.

[1]  T. Pabst,et al.  Leukemic Stem Cell Frequency: A Strong Biomarker for Clinical Outcome in Acute Myeloid Leukemia , 2014, PloS one.

[2]  N. Munshi,et al.  A Multiepitope of XBP1, CD138 and CS1 Peptides Induces Myeloma-Specific Cytotoxic T lymphocytes in T cells of Smoldering Myeloma Patients , 2014, Leukemia.

[3]  P. Coulie,et al.  Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy , 2014, Nature Reviews Cancer.

[4]  S. Parmar,et al.  Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents , 2013, Leukemia.

[5]  Peter A. Jones,et al.  Alterations of immune response of non-small cell lung cancer with Azacytidine , 2013, Oncotarget.

[6]  V. Baladandayuthapani,et al.  Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation. , 2013, Clinical lymphoma, myeloma & leukemia.

[7]  Masakazu Yamamoto,et al.  Long-term Vaccination with Multiple Peptides Derived from Cancer-Testis Antigens Can Maintain a Specific T-cell Response and Achieve Disease Stability in Advanced Biliary Tract Cancer , 2013, Clinical Cancer Research.

[8]  Yangqiu Li,et al.  The role of peptide and DNA vaccines in myeloid leukemia immunotherapy , 2013, Cancer Cell International.

[9]  U. Steidl,et al.  Concise Review: Preleukemic Stem Cells: Molecular Biology and Clinical Implications of the Precursors to Leukemia Stem Cells , 2013, Stem cells translational medicine.

[10]  Quanyi Lu,et al.  DNMT3A mutations and clinical features in Chinese patients with acute myeloid leukemia , 2013, Cancer Cell International.

[11]  R. Wong,et al.  Leukaemic stem cells: drug resistance, metastasis and therapeutic implications. , 2012, The Malaysian journal of pathology.

[12]  Z. Berneman,et al.  Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia , 2012, Leukemia.

[13]  R. Sabo,et al.  Epigenetic induction of adaptive immune response in multiple myeloma: sequential azacitidine and lenalidomide generate cancer testis antigen‐specific cellular immunity , 2012, British journal of haematology.

[14]  M. Maio,et al.  Epigenetic remodelling of gene expression profiles of neoplastic and normal tissues: immunotherapeutic implications , 2012, British Journal of Cancer.

[15]  Yanjie He,et al.  Resistance of leukemic stem-like cells in AML cell line KG1a to natural killer cell-mediated cytotoxicity. , 2012, Cancer letters.

[16]  C. Drake,et al.  Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. , 2012, Current opinion in immunology.

[17]  Fumio Nakahara,et al.  Identification of RHOXF2 (PEPP2) as a cancer-promoting gene by expression cloning. , 2011, International journal of oncology.

[18]  C. Punt,et al.  Cancer immunotherapy – revisited , 2011, Nature Reviews Drug Discovery.

[19]  K. Lucas,et al.  MAGE-A1, MAGE-A3, and NY-ESO-1 can be upregulated on neuroblastoma cells to facilitate cytotoxic T lymphocyte-mediated tumor cell killing , 2011, Cancer Immunology, Immunotherapy.

[20]  A. Dalgleish,et al.  Increased PRAME antigen-specific killing of malignant cell lines by low avidity CTL clones, following treatment with 5-Aza-2′-Deoxycytidine , 2011, Cancer Immunology, Immunotherapy.

[21]  M. Maio,et al.  The biology of cancer testis antigens: Putative function, regulation and therapeutic potential , 2011, Molecular oncology.

[22]  K. Rezvani.  Peptide vaccine therapy for leukemia , 2011, International journal of hematology.

[23]  B. Löwenberg,et al.  Therapeutic advances in acute myeloid leukemia. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  Z. Guo,et al.  Homeobox gene Rhox5 is regulated by epigenetic mechanisms in cancer and stem cells and promotes cancer growth , 2011, Molecular Cancer.

[25]  M. Wilkinson,et al.  The Rhox genes. , 2010, Reproduction.

[26]  H. Goossens,et al.  Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination , 2010, Proceedings of the National Academy of Sciences.

[27]  J. Karbach,et al.  The DNA demethylating agent 5-aza-2'-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. , 2010, Leukemia research.

[28]  O. Ohara,et al.  Identification of Therapeutic Targets for Quiescent, Chemotherapy-Resistant Human Leukemia Stem Cells , 2010, Science Translational Medicine.

[29]  M. Gorry,et al.  Three Epigenetic Drugs Up-Regulate Homeobox Gene Rhox5 in Cancer Cells through Overlapping and Distinct Molecular Mechanisms , 2009, Molecular Pharmacology.

[30]  D. Scheinberg,et al.  Synthetic tumor‐specific breakpoint peptide vaccine in patients with chronic myeloid leukemia and minimal residual disease , 2009, Cancer.

[31]  Martin A. Cheever,et al.  The Prioritization of Cancer Antigens: A National Cancer Institute Pilot Project for the Acceleration of Translational Research , 2009, Clinical Cancer Research.

[32]  Oliver Hofmann,et al.  Genome-wide analysis of cancer/testis gene expression , 2008, Proceedings of the National Academy of Sciences.

[33]  S. Ackerman,et al.  The RHOX5 Homeodomain Protein Mediates Transcriptional Repression of the Netrin-1 Receptor Gene Unc5c* , 2008, Journal of Biological Chemistry.

[34]  H. Aburatani,et al.  Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. , 2005, Genomics.

[35]  M. Wilkinson,et al.  Two novel human X-linked homeobox genes, hPEPP1 and hPEPP2, selectively expressed in the testis. , 2002, Gene.

[36]  T. Akiyama,et al.  WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. , 1994, Blood.