Based on information obtained from multi-omics analyses of DC vaccine-treated ICB-resistant (T cell-depleted) human tumors, Sprooten et al. created DCvax-IT – monocyte-derived DCs pulsed with apoptotic or necrotic tumor cells and stimulated with IFNβ, which recapitulated high immunogenicity and proficient lymph node homing. However, DCvax-IT failed efficacy against T cell-depleted tumors by facilitating CD8+ T cell-suppressive PD-L1+ macrophages in lymph nodes and tumors;a similar observation was made in glioblastoma patients. Combination with anti-PD-L1 (but not anti-PD-1) prevented PD-L1+ TAM accumulation and promoted antitumor T cell responses.
Contributed by Ute Burkhardt
ABSTRACT: Current immunotherapies provide limited benefits against T cell-depleted tumors, calling for therapeutic innovation. Using multi-omics integration of cancer patient data, we predict a type I interferon (IFN) response(HIGH) state of dendritic cell (DC) vaccines, with efficacious clinical impact. However, preclinical DC vaccines recapitulating this state by combining immunogenic cancer cell death with induction of type I IFN responses fail to regress mouse tumors lacking T cell infiltrates. Here, in lymph nodes (LNs), instead of activating CD4(+)/CD8(+) T cells, DCs stimulate immunosuppressive programmed death-ligand 1-positive (PD-L1(+)) LN-associated macrophages (LAMs). Moreover, DC vaccines also stimulate PD-L1(+) tumor-associated macrophages (TAMs). This creates two anatomically distinct niches of PD-L1(+) macrophages that suppress CD8(+) T cells. Accordingly, a combination of PD-L1 blockade with DC vaccines achieves significant tumor regression by depleting PD-L1(+) macrophages, suppressing myeloid inflammation, and de-inhibiting effector/stem-like memory T cells. Importantly, clinical DC vaccines also potentiate T cell-suppressive PD-L1(+) TAMs in glioblastoma patients. We propose that a multimodal immunotherapy and vaccination regimen is mandatory to overcome T cell-depleted tumors.
Author Info: (1) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (2) Laboratory of Cell Stress & Immunity, Department of Cellular
Author Info: (1) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (2) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (3) Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf, Germany. (4) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (5) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (6) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (7) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (8) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (9) Department of Microbiology, Immunology and Transplantation, KU Leuven-University of Leuven, Leuven, Belgium. (10) Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf, Germany. (11) Department of Neurosurgery, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf, Germany. (12) Department of Neurosurgery, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf, Germany. (13) Department of Neurosurgery, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf, Germany. (14) Department of Neurosurgery, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf, Germany. (15) Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Universit Paris Saclay, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellise par la Ligue contre le cancer, Universit de Paris, Sorbonne Universit, Inserm U1138, Institut Universitaire de France, Paris, France. (16) Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Universit Paris Saclay, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellise par la Ligue contre le cancer, Universit de Paris, Sorbonne Universit, Inserm U1138, Institut Universitaire de France, Paris, France. (17) Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Universit Paris Saclay, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellise par la Ligue contre le cancer, Universit de Paris, Sorbonne Universit, Inserm U1138, Institut Universitaire de France, Paris, France. (18) JJP Biologics, Warsaw, Poland. (19) Laboratory for Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. (20) Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (21) Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Universit Paris Saclay, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellise par la Ligue contre le cancer, Universit de Paris, Sorbonne Universit, Inserm U1138, Institut Universitaire de France, Paris, France; Institut du Cancer Paris CARPEM, Department of Biology, Hpital Europen Georges Pompidou, AP-HP, Paris, France. (22) Department of Microbiology, Immunology and Transplantation, KU Leuven-University of Leuven, Leuven, Belgium. (23) Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium; Laboratory of Experimental Neurosurgery and Neuroanatomy, Department of Neurosciences, KU Leuven, Leuven, Belgium; Leuven Brain Institute (LBI), Leuven, Belgium. (24) Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf, Germany. (25) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. Electronic address: abhishek.garg@kuleuven.be.
