Batf3+ DCs and the 4-1BB/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1/PD-L1 blockade efficacy
Andrea Ziblat,
Brendan L. Horton,
Emily F. Higgs,
Ken Hatogai,
Anna Martinez,
Jason W. Shapiro,
Danny E.C. Kim,
YuanYuan Zha,
Randy F. Sweis,
Thomas F. Gajewski
Affiliations
Andrea Ziblat
Department of Pathology, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA
Brendan L. Horton
Department of Pathology, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA
Emily F. Higgs
Department of Pathology, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA
Ken Hatogai
Department of Pathology, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA
Anna Martinez
Department of Pathology, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA
Jason W. Shapiro
Center for Research Informatics, University of Chicago, Chicago, IL 60637, USA
Danny E.C. Kim
Department of Pathology, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA
YuanYuan Zha
Human Immunological Monitoring Facility, University of Chicago, Chicago, IL 60637, USA
Randy F. Sweis
Department of Medicine, University of Chicago, Chicago, IL 60612, USA
Thomas F. Gajewski
Department of Pathology, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA; Department of Medicine, University of Chicago, Chicago, IL 60612, USA; Corresponding author
Summary: The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlates with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME is associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy and indicate a major role for the 4-1BB/4-1BB ligand (4-1BBL) axis during this process.
