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Review
. 2024 May 2;22(1):251.
doi: 10.1186/s12964-024-01626-6.

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

Olga A Sukocheva  1 , Margarita E Neganova  2   3 , Yulia Aleksandrova  2   3 , Jack T Burcher  4 , Elena Chugunova  3 , Ruitai Fan  5 , Edmund Tse  6 , Gautam Sethi  7 , Anupam Bishayee  8 , Junqi Liu  9
Affiliations
Review

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

Olga A Sukocheva et al. Cell Commun Signal. .

Abstract

Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.

Keywords: Apoptosis; Cancer drug resistance; Immunotherapy; Sphingolipids; Sphingosine kinase; Sphingosine-1-phosphate; Tumor necrosis factor-α.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Death receptors (DR) and their ligands intracellular network. Ligands (FasL, TRAIL, TNF-α, TL1) can activate signaling cascades required for the activation of apoptosis and other complex cell responses. TNF-α/TRAIL/FasLs (and other ligands) bind the corresponding receptors (Fas, TRAIL-R1, and TNFR1) and activate apoptosis and necroptosis through interactions between death domains (FADD), TRADD adapter, and various caspases. Both TNFR1 and TNFR2 can trigger the classical NF-κB signaling. Binding of TNF to TNFR1 results in the formation of protein Complex I. Recruitment of IKKα/β through NEMO promotes activation of NF-κB and TAK1 induces MAPK signaling. Activation of the alternative NF-κB pathway is also possible via multiple mechanisms, leading to induction of survival effectors (MAPK and FLIP) which may counterbalance apoptosis (conditional). Complex I formation may also trigger pro-inflammatory and survival gene expression through these signaling pathways. Complex II formation results in the activation of caspase-8 and apoptosis. Should caspase-8 be inhibited, necroptotic cell death can occur instead. Abbreviations: FasL, Fas ligands; TRAIL, TNF-related apoptosis-inducing ligand; TNF-α, tumor necrosis factor-α; TL1, a novel TNF-like cytokine; TNFR1, TNF-α receptor 1; TNFR2, TNF-α receptor 2; FADD, FAS-associated death domain protein; TRADD, TNF receptor type 1-associated death domain protein; NF-κB, nuclear factor-κB; IKKα/β, IκB kinase α/β; NEMO, NF-κB essential modulator; TAK1, TGFβ-activated kinase 1; MAPK, mitogen activated protein kinase; FLIP, FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein
Fig. 2
Fig. 2
The dichotomy of TNF/TNFR effects is associated with activation of antagonizing effects, both promoting and counteracting cell death in immune cells. The resulting effect is defined by the active involvement of intracellular death machinery, which may be overruled by activation of pro-survival effectors. Both pathways lead to production of cytokines and propagation/differentiation of specific immune cells and their recruitment to the site of infection. Abbreviations: DAMPs, damage-associated molecular patterns; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; PAMPs, pathogen-associated molecular pattern molecules; PRR, pattern recognition receptors; TNF-α, tumor necrosis factor-α; TNFR1, tumor necrosis factor-α (TNF-α) receptor-1; Ub, ubiquitin
Fig. 3
Fig. 3
Involvement of TNF-α in the regulation of immune cell differentiation during inflammation and cancer progression. Promoting reprogramming of the TME, TNF-α was suggested to play central role as a connector of inflammation with cancer spreading. Abbreviations: INF-γ, Interferon‐γ; TH1, Type 1 T helper cell; TH2, Type 2 T helper cell; TNF-α, tumor necrosis factor-α
Fig. 4
Fig. 4
Interplay between cancer cell intrinsic factors, TME, and host-related factors that contribute towards the development of TNF/TRAIL resistance and metastasis. Abbreviations: Bcl-2, B-cell lymphoma 2; BMI, body mass index; DCs, dendritic cells; DR, death receptor; FLIP, FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein; IAPs, inhibitors of apoptosis; MiRs, micro ribonucleic acids; ROS, reactive oxygen species; TAMs, tumor-associated macrophages; TNF, tumor necrosis superfamily; TRAIL, TNF-related apoptosis-inducing ligand; Tregs, regulatory T cells
Fig. 5
Fig. 5
The sphingolipid signaling pathway. Various sphingolipids molecules (second messengers) can be derived from the membrane lipid sphingomyelin by sphingomyelinase (SMase) and metabolised by a “rheostat”-forming network which regulate homeostasis. Accumulation of ceramide and sphingosine can tip the balance towards apoptosis and other types of cell death. Activation of SphK1/2, production of S1P (and activation of S1P receptors), and/or S1P degradation by S1P lyase to hexadecenal and ethanolamine phosphate result in pro-survival and growth-promoting effects. Sphingomyelin membrane content can be restored through activation of sphingomyelin synthase (SM Synthase), which can also help to minimise the content of ceramide. The amount of sphingosine can be increased via inhibition of SphK1/2 and or through activation of S1P phosphatase
Fig. 6
Fig. 6
Dichotomy of TNF-α–induced signaling in cancers is hypothetically linked to sphingolipid balance where the relative amounts of ceramide and S1P cause cell proliferation, survival, or death. Stressed cells can increase ceramide in response to TNF-α, resulting in growth arrest and apoptosis. However, in some cells TNF-α can activate SphK and mitigate its pro-apoptotic ability via production of growth-stimulating S1P and activation of S1PR1-5. Abbreviations: CerS, ceramidase; GPCR, G-protein coupled receptor; HDAC1/2, histone deacetylase 1 and 2; hTERT, human telomerase reverse transcriptase gene; JNK, c-Jun NH2-terminal kinase; PPARγ, peroxisome proliferator-activated receptor-γ; SMase, sphingomyelinase
Fig. 7
Fig. 7
The conceptual model for the regulation of immune T cell responses by the SphK/S1P/S1PR axis during cancer progression. Sphingolipids were shown to impact cancer cell recognition and killing by immune cells at different levels. Abbreviations: PD-1, programmed death-1; PD-L1, programmed death-1 (PD-1) ligand 1; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; S1P1/S1P3, sphingosine-1-phosphate receptor 1 and 3; SphK, sphingosine kinase; WNT, wingless-related integration site
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