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

Abstract

Resistance to cell death is a hallmark of cancer. Immunotherapy, particularly immune checkpoint blockade therapy, drives immunemediated 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-a and IFN-g 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-a and IFN-g 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-a and IFN-g triggered activation of gasdermin D, gasdermin E, caspase-8, caspase-3, caspase-7, and MLKL. Furthermore, the intratumoral administration of TNF-a and IFN-g suppressed the growth of transplanted xenograft tumors in an NSG mouse model. Overall, this study shows that PANoptosis, induced by synergism of TNF-a and IFN-g, is an important mechanism to kill cancer cells and suppress tumor growth that could be therapeutically targeted.

The Transcription Factor IRF9 Promotes Colorectal Cancer via Modulating the IL-6/STAT3 Signaling Axis

“…In addition to inflammation, dysregulation of or acquired resistance to cell death can regulate tumorigenesis. The IFN signaling pathway is known to be important in this process; for example, IRF1 acts as a tumor suppressor in a mouse model of CRC and in human cancer cells by promoting PANoptosis [ 21 , 22 ]. PANoptosis is an innate immune inflammatory programmed cell death pathway dependent on PANoptosomes, caspase(s)-containing complexes with or without inflammasome components and RHIM-containing proteins [ 15 , 21 , 22 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

“…In the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced mouse model of CRC, IRF3-deficient mice develop more tumors [ 19 ], while type I IFN receptor (IFNAR)-deficient mice develop a similar number of tumors when compared with WT mice [ 20 ]. Additionally, we recently reported the tumor suppressive function of IRF1 during CRC, as IRF1 potentiates inflammatory cell death, PANoptosis, in cancer cells [ 21 , 22 ]. STAT1 and STAT2, two of the key components of the ISGF3 complex that regulates the production of many ISGs, are also reported to have distinctive functions in CRC [ 23 , 24 , 25 ].…”

Coronavirus Infection-Associated Cell Death Signaling and Potential Therapeutic Targets

“…RIPK3-mediated oligomerization of MLKL produces necroptosis [87][88][89]. Pyroptosis and necroptosis are lytic death processes in which cytokines and other cellular components are released [85,[89][90][91].…”

Innate Immunity and Cell Death in Alzheimer's Disease

“…Recent studies have found extensive crosstalk between programmed cell death pathways, establishing the concept of PANoptosis (pyroptosis, apoptosis, necroptosis) (Gurung et al, 2014;Kuriakose et al, 2016;Lamkanfi et al, 2008;Lee et al, 2020Lee et al, , 2021bMalireddi et al, 2010Malireddi et al, , 2021Place et al, 2021). Although inflammasome activation is primarily associated with gasdermin D (GSDMD)-mediated pyroptosis, there is emerging evidence of the contribution of inflammasome components in driving PANoptosis (Christgen et al, 2020;Gurung et al, 2014;Kesavardhana et al, 2020;Kuriakose et al, 2016;Lee et al, 2020Lee et al, , 2021bMalireddi et al, 2020Malireddi et al, , 2021Place et al, 2021;Zheng et al, 2020).…”