Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells.
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.


CONCLUSIONS
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.
Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
Alfonso R
AR
Sánchez-Paulete
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. Department of Biochemistry, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
Francisco J
FJ
Cueto
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
María
M
Martínez-López
Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
Sara
S
Labiano
Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
Aizea
A
Morales-Kastresana
University Clinic, University of Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
María E
ME
Rodríguez-Ruiz
Bristol-Myers Squibb, Princeton, New Jersey.
Maria
M
Jure-Kunkel
Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
Arantza
A
Azpilikueta
Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
M Angela
MA
Aznar
Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
José I
JI
Quetglas
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. imelero@unav.es dsancho@cnic.es.
David
D
Sancho
Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain. University Clinic, University of Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain. imelero@unav.es dsancho@cnic.es.
Ignacio
I
Melero
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology
D000911:Antibodies, Monoclonal; D050976:Basic-Leucine Zipper Transcription Factors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012097:Repressor Proteins; C533289:SNFT protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9