Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells

Despite aggressive conventional therapy, glioblastoma (GBM) remains uniformly lethal. Immunotherapy, in which the immune system is harnessed to specifically attack malignant cells, offers a treatment option with less toxicity. The expression of cytomegalovirus (CMV) antigens in GBM presents a unique...

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Vydané v:	Clinical cancer research Ročník 20; číslo 10; s. 2684
Hlavní autori:	Nair, Smita K, De Leon, Gabriel, Boczkowski, David, Schmittling, Robert, Xie, Weihua, Staats, Janet, Liu, Rebecca, Johnson, Laura A, Weinhold, Kent, Archer, Gary E, Sampson, John H, Mitchell, Duane A
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 15.05.2014
Predmet:	Blotting, Western Cells, Cultured Coculture Techniques Cytokines - immunology Cytokines - metabolism Cytomegalovirus - immunology Cytomegalovirus - metabolism Cytomegalovirus - physiology Cytotoxicity Tests, Immunologic - methods Cytotoxicity, Immunologic - immunology Dendritic Cells - immunology Dendritic Cells - metabolism Female Flow Cytometry Glioblastoma - immunology Glioblastoma - pathology Glioblastoma - virology Humans Lymphocyte Activation - immunology Male Middle Aged Phosphoproteins - genetics Phosphoproteins - immunology Phosphoproteins - metabolism RNA, Viral - genetics RNA, Viral - immunology T-Lymphocytes - immunology T-Lymphocytes, Cytotoxic - immunology Tumor Cells, Cultured Viral Matrix Proteins - genetics Viral Matrix Proteins - immunology Viral Matrix Proteins - metabolism Young Adult
ISSN:	1557-3265, 1557-3265
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Abstract	Despite aggressive conventional therapy, glioblastoma (GBM) remains uniformly lethal. Immunotherapy, in which the immune system is harnessed to specifically attack malignant cells, offers a treatment option with less toxicity. The expression of cytomegalovirus (CMV) antigens in GBM presents a unique opportunity to target these viral proteins for tumor immunotherapy. Although the presence of CMV within malignant gliomas has been confirmed by several laboratories, its relevance as an immunologic target in GBM has yet to be established. The objective of this study was to explore whether T cells stimulated by CMV pp65 RNA-transfected dendritic cells (DC) target and eliminate autologous GBM tumor cells in an antigen-specific manner. T cells from patients with GBM were stimulated with autologous DCs pulsed with CMV pp65 RNA, and the function of the effector CMV pp65-specific T cells was measured. In this study, we demonstrate the ability to elicit CMV pp65-specific immune responses in vitro using RNA-pulsed autologous DCs generated from patients with newly diagnosed GBM. Importantly, CMV pp65-specific T cells lyse autologous, primary GBM tumor cells in an antigen-specific manner. Moreover, T cells expanded in vitro using DCs pulsed with total tumor RNA demonstrated a 10- to 20-fold expansion of CMV pp65-specific T cells as assessed by tetramer analysis and recognition and killing of CMV pp65-expressing target cells. These data collectively demonstrate that CMV-specific T cells can effectively target glioblastoma tumor cells for immunologic killing and support the rationale for the development of CMV-directed immunotherapy in patients with GBM.
AbstractList	Despite aggressive conventional therapy, glioblastoma (GBM) remains uniformly lethal. Immunotherapy, in which the immune system is harnessed to specifically attack malignant cells, offers a treatment option with less toxicity. The expression of cytomegalovirus (CMV) antigens in GBM presents a unique opportunity to target these viral proteins for tumor immunotherapy. Although the presence of CMV within malignant gliomas has been confirmed by several laboratories, its relevance as an immunologic target in GBM has yet to be established. The objective of this study was to explore whether T cells stimulated by CMV pp65 RNA-transfected dendritic cells (DC) target and eliminate autologous GBM tumor cells in an antigen-specific manner.PURPOSEDespite aggressive conventional therapy, glioblastoma (GBM) remains uniformly lethal. Immunotherapy, in which the immune system is harnessed to specifically attack malignant cells, offers a treatment option with less toxicity. The expression of cytomegalovirus (CMV) antigens in GBM presents a unique opportunity to target these viral proteins for tumor immunotherapy. Although the presence of CMV within malignant gliomas has been confirmed by several laboratories, its relevance as an immunologic target in GBM has yet to be established. The objective of this study was to explore whether T cells stimulated by CMV pp65 RNA-transfected dendritic cells (DC) target and eliminate autologous GBM tumor cells in an antigen-specific manner.T cells from patients with GBM were stimulated with autologous DCs pulsed with CMV pp65 RNA, and the function of the effector CMV pp65-specific T cells was measured.EXPERIMENTAL DESIGNT cells from patients with GBM were stimulated with autologous DCs pulsed with CMV pp65 RNA, and the function of the effector CMV pp65-specific T cells was measured.In this study, we demonstrate the ability to elicit CMV pp65-specific immune responses in vitro using RNA-pulsed autologous DCs generated from patients with newly diagnosed GBM. Importantly, CMV pp65-specific T cells lyse autologous, primary GBM tumor cells in an antigen-specific manner. Moreover, T cells expanded in vitro using DCs pulsed with total tumor RNA demonstrated a 10- to 20-fold expansion of CMV pp65-specific T cells as assessed by tetramer analysis and recognition and killing of CMV pp65-expressing target cells.RESULTSIn this study, we demonstrate the ability to elicit CMV pp65-specific immune responses in vitro using RNA-pulsed autologous DCs generated from patients with newly diagnosed GBM. Importantly, CMV pp65-specific T cells lyse autologous, primary GBM tumor cells in an antigen-specific manner. Moreover, T cells expanded in vitro using DCs pulsed with total tumor RNA demonstrated a 10- to 20-fold expansion of CMV pp65-specific T cells as assessed by tetramer analysis and recognition and killing of CMV pp65-expressing target cells.These data collectively demonstrate that CMV-specific T cells can effectively target glioblastoma tumor cells for immunologic killing and support the rationale for the development of CMV-directed immunotherapy in patients with GBM.CONCLUSIONThese data collectively demonstrate that CMV-specific T cells can effectively target glioblastoma tumor cells for immunologic killing and support the rationale for the development of CMV-directed immunotherapy in patients with GBM. Despite aggressive conventional therapy, glioblastoma (GBM) remains uniformly lethal. Immunotherapy, in which the immune system is harnessed to specifically attack malignant cells, offers a treatment option with less toxicity. The expression of cytomegalovirus (CMV) antigens in GBM presents a unique opportunity to target these viral proteins for tumor immunotherapy. Although the presence of CMV within malignant gliomas has been confirmed by several laboratories, its relevance as an immunologic target in GBM has yet to be established. The objective of this study was to explore whether T cells stimulated by CMV pp65 RNA-transfected dendritic cells (DC) target and eliminate autologous GBM tumor cells in an antigen-specific manner. T cells from patients with GBM were stimulated with autologous DCs pulsed with CMV pp65 RNA, and the function of the effector CMV pp65-specific T cells was measured. In this study, we demonstrate the ability to elicit CMV pp65-specific immune responses in vitro using RNA-pulsed autologous DCs generated from patients with newly diagnosed GBM. Importantly, CMV pp65-specific T cells lyse autologous, primary GBM tumor cells in an antigen-specific manner. Moreover, T cells expanded in vitro using DCs pulsed with total tumor RNA demonstrated a 10- to 20-fold expansion of CMV pp65-specific T cells as assessed by tetramer analysis and recognition and killing of CMV pp65-expressing target cells. These data collectively demonstrate that CMV-specific T cells can effectively target glioblastoma tumor cells for immunologic killing and support the rationale for the development of CMV-directed immunotherapy in patients with GBM.
Author	Sampson, John H Johnson, Laura A Boczkowski, David Weinhold, Kent Archer, Gary E Mitchell, Duane A De Leon, Gabriel Schmittling, Robert Xie, Weihua Nair, Smita K Staats, Janet Liu, Rebecca
Author_xml	– sequence: 1 givenname: Smita K surname: Nair fullname: Nair, Smita K email: smita.nair@duke.edu organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina smita.nair@duke.edu – sequence: 2 givenname: Gabriel surname: De Leon fullname: De Leon, Gabriel organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina – sequence: 3 givenname: David surname: Boczkowski fullname: Boczkowski, David organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina – sequence: 4 givenname: Robert surname: Schmittling fullname: Schmittling, Robert organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina – sequence: 5 givenname: Weihua surname: Xie fullname: Xie, Weihua organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina – sequence: 6 givenname: Janet surname: Staats fullname: Staats, Janet organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina – sequence: 7 givenname: Rebecca surname: Liu fullname: Liu, Rebecca organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina – sequence: 8 givenname: Laura A surname: Johnson fullname: Johnson, Laura A organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina – sequence: 9 givenname: Kent surname: Weinhold fullname: Weinhold, Kent organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina – sequence: 10 givenname: Gary E surname: Archer fullname: Archer, Gary E organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina – sequence: 11 givenname: John H surname: Sampson fullname: Sampson, John H organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina – sequence: 12 givenname: Duane A surname: Mitchell fullname: Mitchell, Duane A organization: Authors' Affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina
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SubjectTerms	Blotting, Western Cells, Cultured Coculture Techniques Cytokines - immunology Cytokines - metabolism Cytomegalovirus - immunology Cytomegalovirus - metabolism Cytomegalovirus - physiology Cytotoxicity Tests, Immunologic - methods Cytotoxicity, Immunologic - immunology Dendritic Cells - immunology Dendritic Cells - metabolism Female Flow Cytometry Glioblastoma - immunology Glioblastoma - pathology Glioblastoma - virology Humans Lymphocyte Activation - immunology Male Middle Aged Phosphoproteins - genetics Phosphoproteins - immunology Phosphoproteins - metabolism RNA, Viral - genetics RNA, Viral - immunology T-Lymphocytes - immunology T-Lymphocytes, Cytotoxic - immunology Tumor Cells, Cultured Viral Matrix Proteins - genetics Viral Matrix Proteins - immunology Viral Matrix Proteins - metabolism Young Adult
Title	Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells
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