T cell cross-priming by PD-L1+ type 1 conventional dendritic cells mediates the antitumor efficacy of a PD-L1×4-1BB bispecific antibody
(1) Luri-Rey C (2) Rodrguez I (3) Arrieta-Aranzueque S (4) Guillamn DR (5) Vercher E (6) Soria N (7) Molero-Glez P (8) Cuesta R (9) Gomis G (10) Azpilikueta A (11) Bolaos E (12) Manzanal A (13) Garasa S (14) Kaisho T (15) Alexandru R (16) Domnguez PP (17) Calvo A (18) Exposito F (19) Heras-Murillo I (20) Sancho D (21) Capello M (22) Pencheva N (23) Berraondo P (24) de Andrea C (25) Jure-Kunkel M (26) Teijeira ç (27) Melero I
Using genetic deletion, Luri-Rey et al. showed that in mouse models, the therapeutic efficacy of a PD-L×4-1BB bispecific antibody required PD-L1 expression on cDC1s, but not tumor cells. TdLN removal prior to therapy impaired tumor regression. PD-L1×4-1BB therapy enhanced tumor-antigen cross-presentation through IL-12, 4-1BB costimulation, and cDC1 licensing by CD40L. Therapy boosted cDC1–T cell contacts, T cell activation transcriptional programs, and tumor antigen-specific CD8+ T cell proliferation. cDC1 and activated CD8+ T cell infiltration and adjacency were increased in treated tumors. Flt3L increased DC prevalence to promote efficacy.
Contributed by Paula Hochman
(1) Luri-Rey C (2) Rodrguez I (3) Arrieta-Aranzueque S (4) Guillamn DR (5) Vercher E (6) Soria N (7) Molero-Glez P (8) Cuesta R (9) Gomis G (10) Azpilikueta A (11) Bolaos E (12) Manzanal A (13) Garasa S (14) Kaisho T (15) Alexandru R (16) Domnguez PP (17) Calvo A (18) Exposito F (19) Heras-Murillo I (20) Sancho D (21) Capello M (22) Pencheva N (23) Berraondo P (24) de Andrea C (25) Jure-Kunkel M (26) Teijeira ç (27) Melero I
Using genetic deletion, Luri-Rey et al. showed that in mouse models, the therapeutic efficacy of a PD-L×4-1BB bispecific antibody required PD-L1 expression on cDC1s, but not tumor cells. TdLN removal prior to therapy impaired tumor regression. PD-L1×4-1BB therapy enhanced tumor-antigen cross-presentation through IL-12, 4-1BB costimulation, and cDC1 licensing by CD40L. Therapy boosted cDC1–T cell contacts, T cell activation transcriptional programs, and tumor antigen-specific CD8+ T cell proliferation. cDC1 and activated CD8+ T cell infiltration and adjacency were increased in treated tumors. Flt3L increased DC prevalence to promote efficacy.
Contributed by Paula Hochman
ABSTRACT: Bispecific antibodies that conditionally engage costimulatory receptors aim to enhance antitumor T cell immunity while limiting systemic toxicity. We investigated mechanisms underlying the clinical performance of a PD-L1_4-1BB bispecific antibody. Therapeutic efficacy of PD-L1_4-1BB was largely independent of PD-L1 expression on malignant cells but waned in Batf3(-/-) mice or upon depletion of type 1 conventional dendritic cells (cDC1s). cDC1-specific deletion of PD-L1 markedly limited tumor control. PD-L1_4-1BB enhanced proliferation of tumor-antigen-specific CD8(+) T cells through mechanisms dependent on cross-presentation, the presence of interleukin (IL)-12, 4-1BB costimulation, and CD40L-mediated cDC1 licensing. PD-L1_4-1BB increased cDC1-T cell contacts, which promoted transcriptional programs associated with T cell activation and proliferation. Treated tumors exhibited increased infiltration and spatial proximity of cDC1s and activated CD8(+) T cells. Accordingly, increasing dendritic-cell abundance via Flt3L further enhanced tumor control. Thus, cDC1-T cell interactions are central to PD-L1_4-1BB activity, with antigen cross-presentation, dendritic-cell licensing, and IL-12 and 4-1BB costimulation converging to promote antitumor immunity.
Author Info:
(1) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigacin
Biomdica en Red de Cncer (CIBERONC), Madrid, Spain. (2) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. (3) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. (4) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. (5) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. (6) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (7) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. (8) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. (9) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. (10) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (11) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (12) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. (13) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. (14) Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan. (15) Department of Pathology, Anatomy and Physiology, Schools of Medicine and Sciences, University of Navarra and Clnica Universidad de Navarra, Pamplona, Spain. (16) Department of Pathology, Anatomy and Physiology, Schools of Medicine and Sciences, University of Navarra and Clnica Universidad de Navarra, Pamplona, Spain. (17) Department of Pathology, Anatomy and Physiology, Schools of Medicine and Sciences, University of Navarra and Clnica Universidad de Navarra, Pamplona, Spain. (18) Program in Solid Tumors, CIMA Universidad de Navarra, Pamplona, Spain. (19) Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (20) Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (21) Genmab BV, Utrecht, the Netherlands. (22) Genmab BV, Utrecht, the Netherlands. (23) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain. (24) Department of Pathology, Anatomy and Physiology, Schools of Medicine and Sciences, University of Navarra and Clnica Universidad de Navarra, Pamplona, Spain. (25) Genmab U.S. Inc., Princeton, NJ, USA. (26) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain. Electronic address: ateijeiras@unav.es. (27) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigacin Biomdica en Red de Cncer (CIBERONC), Madrid, Spain; Nuffield Department of Medicine, University of Oxford, Oxford, UK; Departments of Immunology and Oncology, Clnica Universidad de Navarra, Pamplona, Spain. Electronic address: imelero@unav.es.
