Inflammatory Cell Death, PANoptosis, Mediated by Cytokines in Diverse Cancer Lineages Inhibits Tumor Growth.

Publication date: Jul 21, 2021

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.

Concepts Keywords
Cancer Cell signaling
Eliminate Cytokines
Necroptosis Caspases
Therapy Immunology
Xenograft Programmed cell death
Medical specialties
Branches of biology
Pyroptosis
Tumor necrosis factor
Apoptosis

Semantics

Type Source Name
disease MESH Cancer
disease MESH Growth
drug DRUGBANK Spinosad
disease MESH lung cancer
disease MESH melanoma
pathway KEGG Melanoma
disease MESH leukemia
pathway REACTOME Programmed Cell Death
pathway KEGG Apoptosis
pathway KEGG Necroptosis

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *