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UnlabelledWeak 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.SignificanceImmunotherapy 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.

Original publication




Journal article


Cancer discovery

Publication Date





71 - 79


Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.


Dendritic Cells, Cell Line, Tumor, Animals, Mice, Transgenic, Humans, Mice, Melanoma, Experimental, Repressor Proteins, Antibodies, Monoclonal, Immunotherapy, Lymphocyte Activation, Basic-Leucine Zipper Transcription Factors, Programmed Cell Death 1 Receptor, Tumor Necrosis Factor Receptor Superfamily, Member 9