Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells
UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are esse...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Publication date: | 2016 |
| Country: | España |
| Institution: | Instituto de Salud Carlos III (ISCIII) |
| Repository: | Repisalud |
| Language: | English |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/9721 |
| Online Access: | http://hdl.handle.net/20.500.12105/9721 |
| Access Level: | Open access |
| Keyword: | Animals Antibodies, Monoclonal Basic-Leucine Zipper Transcription Factors Cell Line, Tumor Dendritic Cells Humans Immunotherapy Lymphocyte Activation Melanoma, Experimental Mice Mice, Transgenic Programmed Cell Death 1 Receptor Repressor Proteins Tumor Necrosis Factor Receptor Superfamily, Member 9 |
| _version_ | 1878740099524460544 |
|---|---|
| author | Sánchez-Paulete, Alfonso R |
| author2 | Cueto, Francisco J. Martínez-López, María Labiano, Sara Morales-Kastresana, Aizea Rodríguez-Ruiz, María E Jure-Kunkel, Maria Azpilikueta, Arantza Aznar, M Angela Quetglas, José I Sancho, David Melero, Ignacio |
| author2_role | author author author author author author author author author author author |
| author_browse | Aznar, M Angela Azpilikueta, Arantza Cueto, Francisco J. Jure-Kunkel, Maria Labiano, Sara Martínez-López, María Melero, Ignacio Morales-Kastresana, Aizea Quetglas, José I Rodríguez-Ruiz, María E Sancho, David Sánchez-Paulete, Alfonso R |
| author_facet | Sánchez-Paulete, Alfonso R Cueto, Francisco J. Martínez-López, María Labiano, Sara Morales-Kastresana, Aizea Rodríguez-Ruiz, María E Jure-Kunkel, Maria Azpilikueta, Arantza Aznar, M Angela Quetglas, José I Sancho, David Melero, Ignacio |
| author_role | author |
| collection | Repisalud |
| description | UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas, whereas this function was lost in Batf3(-/-) mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects. SIGNIFICANCE: Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory mAbs. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_cd735b1f3fcba0bbdd7c8564d117837f |
| institution | Instituto de Salud Carlos III (ISCIII) |
| instname_str | Instituto de Salud Carlos III (ISCIII) |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:repisalud.isciii.es:20.500.12105/9721 |
| publishDate | 2016 |
| publishDateSort | 2016 |
| publisher | American Association for Cancer Research (AACR) |
| publisherStr | American Association for Cancer Research (AACR) |
| reponame_str | Repisalud |
| spelling | Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells Sánchez-Paulete, Alfonso R Cueto, Francisco J. Martínez-López, María Labiano, Sara Morales-Kastresana, Aizea Rodríguez-Ruiz, María E Jure-Kunkel, Maria Azpilikueta, Arantza Aznar, M Angela Quetglas, José I Sancho, David Melero, Ignacio Animals Antibodies, Monoclonal Basic-Leucine Zipper Transcription Factors Cell Line, Tumor Dendritic Cells Humans Immunotherapy Lymphocyte Activation Melanoma, Experimental Mice Mice, Transgenic Programmed Cell Death 1 Receptor Repressor Proteins Tumor Necrosis Factor Receptor Superfamily, Member 9 UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas, whereas this function was lost in Batf3(-/-) mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects. SIGNIFICANCE: Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory mAbs. American Association for Cancer Research (AACR) http://hdl.handle.net/20.500.12105/9721 |
| spellingShingle | Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells Sánchez-Paulete, Alfonso R Animals Antibodies, Monoclonal Basic-Leucine Zipper Transcription Factors Cell Line, Tumor Dendritic Cells Humans Immunotherapy Lymphocyte Activation Melanoma, Experimental Mice Mice, Transgenic Programmed Cell Death 1 Receptor Repressor Proteins Tumor Necrosis Factor Receptor Superfamily, Member 9 |
| title | Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells |
| title_full | Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells |
| title_fullStr | Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells |
| title_full_unstemmed | Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells |
| title_short | Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells |
| title_sort | Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells |
| topic | Animals Antibodies, Monoclonal Basic-Leucine Zipper Transcription Factors Cell Line, Tumor Dendritic Cells Humans Immunotherapy Lymphocyte Activation Melanoma, Experimental Mice Mice, Transgenic Programmed Cell Death 1 Receptor Repressor Proteins Tumor Necrosis Factor Receptor Superfamily, Member 9 |
| topic_facet | Animals Antibodies, Monoclonal Basic-Leucine Zipper Transcription Factors Cell Line, Tumor Dendritic Cells Humans Immunotherapy Lymphocyte Activation Melanoma, Experimental Mice Mice, Transgenic Programmed Cell Death 1 Receptor Repressor Proteins Tumor Necrosis Factor Receptor Superfamily, Member 9 |
| url | http://hdl.handle.net/20.500.12105/9721 |