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Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy
- Source :
- Sci Immunol, Science Immunology, Vol. 6, No 61 (2021) P. eabi7083
- Publication Year :
- 2021
- Publisher :
- American Association for the Advancement of Science (AAAS), 2021.
-
Abstract
- Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40-treatment in mice as a model of Th1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-𝛾 and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-𝛾 were not toxic themselves, but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways following anti-PD-1 and anti-CTLA4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in Th1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.
- Subjects :
- 0301 basic medicine
Liver toxicity
Kupffer Cells
Neutrophils
medicine.medical_treatment
Programmed Cell Death 1 Receptor
Immunology
MEDLINE
Mice, Transgenic
Inflammation
ddc:616.07
Article
03 medical and health sciences
0302 clinical medicine
Cancer immunotherapy
Neoplasms
medicine
Animals
Humans
CTLA-4 Antigen
CD40 Antigens
Adverse effect
Immune Checkpoint Inhibitors
ddc:616
Hepatology
Effector
business.industry
Macrophages
Gastroenterology
General Medicine
Immunotherapy
3. Good health
Cancer treatment
030104 developmental biology
Liver
030220 oncology & carcinogenesis
Toxicity
Cancer research
Cytokines
medicine.symptom
610 Medizin und Gesundheit
business
Subjects
Details
- ISSN :
- 24709468
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Science Immunology
- Accession number :
- edsair.doi.dedup.....2b9db22b1b089ff465f17caa910096aa