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328 Batf3 dendritic cells and 4–1BB/4–1BB ligand axis are required at the effector phase within the tumor microenvironment for anti-PD-L1 efficacy
  1. Andrea Ziblat1,
  2. Brendan Horton2,
  3. Emily Higgs1,
  4. Ken Hatogai1 and
  5. Thomas Gajewski1
  1. 1University of Chicago, Chicago, IL, USA
  2. 2MIT, Cambridge, MA, USA


Background PD-1/PD-L1 blockade has shown clinical benefit across many cancer types. However, a large fraction of patients are resistant to immune checkpoint blockade therapy and others eventually relapse. Understanding the mechanisms involved in αPD1/PD-L1 immunotherapy efficacy may enable new strategies for improving clinical outcomes. Given that Batf3-lineage dendritic cells (DCs) are needed for spontaneous T cell priming in the tumor-draining lymph node and for recruitment of effector CD8+ T cells to the tumor, in the current work we examined whether Batf3+ DCs are also required during the effector phase of the anti-tumor immune response at the time of anti-PD-L1 administration for therapeutic efficacy.

Methods We utilized the B16-SIY melanoma model, CD11c-DTR-GFP, and CD11c-DTR-GFP/Batf3 KO bone marrow chimeras to study the role Batf3+ DCs play during anti-PD-L1 immunotherapy. To focus on the effector phase of the immune response, we depleted CD11c+ cells with diphtheria toxin from day seven of tumor injection while simultaneously blocking new T cell entry with FTY720. As flow cytometry revealed high 4-1BBL expression on intratumoral Batf3-DCs, 4-1BB KO mice and anti-4-1BBL blocking antibodies were used. Tumor growth and phenotypic analysis of the tumor infiltrate were evaluated.

Results Strikingly, we observed that CD11c+ cells, and specifically Batf3+ DCs, were required in the tumor prior to αPD-L1 treatment for immunotherapy efficacy. The normal intratumoral expansion of antigen (Ag)-specific CD8+ tumor-infiltrating T cells (TILs) and increased ratio between Ag-specific CD8+ TILs and regulatory T cells following anti-PD-L1 therapy was eliminated with Batf3+ DC depletion. Batf3+ DCs expressed high levels of 4-1BBL, and increased expression of 4-1BB on antigen-specific CD8+ TILs upon αPD-L1 treatment required Batf3+ DCs. Mechanistic experiments confirmed a requirement for 4-1BB expression on immune cells for αPD-L1 efficacy, and blocking antibodies against 4-1BBL eliminated anti-PD-L1 efficacy as well. Using appropriate bone marrow chimeras, agonistic 4-1BB antibodies were sufficient to bypass the need for CD11c+ DCs at the effector phase for tumor control. In human melanoma samples, co-localization of Batf3+ DCs and CD8+ T cells was observed in T cell-inflamed tumors, which correlated with anti-PD-1 efficacy in metastatic melanoma.

Conclusions Our results indicate that Batf3+ DCs are necessary during the effector phase of the anti-tumor immune response for anti-PD-L1 efficacy to occur, at least in part through 4-1BB/4-1BBL-mediated reinvigoration of Ag-specific CD8+ TILs.

Ethics Approval The study obtained ethics approval, IRB protocol 15-0837.

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