Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 12, Issue 561, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aba5464
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Funding
- Swiss National Science Foundation [310030-172978]
- Hochspezialisierte Medizin Schwerpunkt Immunologie (HSM-2-Immunologie)
- Clinical Research Priority Program CYTIMM-Z of the University of Zurich
- Swiss Cancer Research grant [KFS-4136-02-2017]
- Swiss Cancer MD-PhD fellowship [MDPhD-3557-06-2015]
- Olga Mayenfisch Stiftung
- EMDO Stiftung
- Young Talents in Clinical Research Fellowship by the Swiss Academy of Medical Sciences
- Bangerter Foundation [YTCR 32/18]
- Fritz Rohrer-Fonds
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Tumor-infiltrating dendritic cells (DCs) correlate with effective anticancer immunity and improved responsiveness to anti-PD-1 checkpoint immunotherapy. However, the drivers of DC expansion and intratumoral accumulation are ill-defined. We found that interleukin-2 (IL-2) stimulated DC formation through innate and adaptive lymphoid cells in mice and humans, and this increase in DCs improved anticancer immunity. Administration of IL-2 to humans within a clinical trial and of IL-2 receptor (IL-2R)-biased IL-2 to mice resulted in pronounced expansion of type 1 DCs, including migratory and cross-presenting subsets, and type 2 DCs, although neither DC precursors nor mature DCs had functional IL-2Rs. In mechanistic studies, IL-2 signals stimulated innate lymphoid cells, natural killer cells, and T cells to synthesize the cytokines FLT3L, CSF-2, and TNF. These cytokines redundantly caused DC expansion and activation, which resulted in improved antigen processing and correlated with favorable anticancer responses in mice and patients. Thus, IL-2 immunotherapy-mediated stimulation of DCs contributes to anticancer immunity by rendering tumors more immunogenic.
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