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Inflammatory Cell Death, PANoptosis, Mediated by Cytokines in Diverse Cancer Lineages Inhibits Tumor Growth
- Source :
- Immunohorizons
- Publication Year :
- 2021
- Publisher :
- The American Association of Immunologists, 2021.
-
Abstract
- Resistance to cell death is a hallmark of cancer. Immunotherapy, particularly immune checkpoint blockade therapy, drives immune-mediated cell death and has greatly improved treatment outcomes for some patients with cancer, but it often fails clinically. Its success relies on the cytokines and cytotoxic functions of effector immune cells to bypass the resistance to cell death and eliminate cancer cells. However, the specific cytokines capable of inducing cell death in tumors and the mechanisms that connect cytokines to cell death across cancer cell types remain unknown. In this study, we analyzed expression of several cytokines that are modulated in tumors and found correlations between cytokine expression and mortality. Of several cytokines tested for their ability to kill cancer cells, only TNF-α and IFN-γ together were able to induce cell death in 13 distinct human cancer cell lines derived from colon and lung cancer, melanoma, and leukemia. Further evaluation of the specific programmed cell death pathways activated by TNF-α and IFN-γ in these cancer lines identified PANoptosis, a form of inflammatory cell death that was previously shown to be activated by contemporaneous engagement of components from pyroptosis, apoptosis, and/or necroptosis. Specifically, TNF-α and IFN-γ triggered activation of gasdermin D, gasdermin E, caspase-8, caspase-3, caspase-7, and MLKL. Furthermore, the intratumoral administration of TNF-α and IFN-γ suppressed the growth of transplanted xenograft tumors in an NSG mouse model. Overall, this study shows that PANoptosis, induced by synergism of TNF-α and IFN-γ, is an important mechanism to kill cancer cells and suppress tumor growth that could be therapeutically targeted.
- Subjects :
- Programmed cell death
Necroptosis
medicine.medical_treatment
Immunology
Immunogenic Cell Death
Article
Interferon-gamma
Mice
Cell Line, Tumor
Neoplasms
Animals
Humans
Immunology and Allergy
Medicine
Cytotoxic T cell
Tumor Necrosis Factor-alpha
business.industry
Pyroptosis
Cancer
General Medicine
Immunotherapy
medicine.disease
Xenograft Model Antitumor Assays
Apoptosis
Cancer cell
Cancer research
business
Signal Transduction
Subjects
Details
- ISSN :
- 25737732
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- ImmunoHorizons
- Accession number :
- edsair.doi.dedup.....075e13b7b4e44eac50f35ac28f087423