Necroptosis-driving genesRIPK1, RIPK3andMLKL-pare associated with intratumoral CD3+and CD8+T cell density and predict prognosis in hepatocellular carcinoma

Nicolè, Lorenzo; Sanavia, Tiziana; Cappellesso, Rocco; Maffeis, Valeria; Akiba, Jun; Kawahara, Akihiko; Naito, Yoshiki; Radu, Claudia; Simioni, Paolo; Serafin, Davide; Cortese, Giuliana; Guido, Maria; Zanus, Giacomo; Yano, Hirohisa; Fassina, Ambrogio

doi:10.1136/jitc-2021-004031

Cited by 37 publications

(31 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 154 Recently, a study has shown that the expression of RIPK1, RIPK3, and MLKL was linked to better overall survival in HCC. 155 Furthermore, methylation near the transcription start site silences RIPK3 expression in cancer cells. Therefore, hypomethylation drug treatment can improve prognosis by restoring RIPK3 expression and increasing sensitivity to chemotherapeutic agents.…”

Section: Overview Of Necroptosismentioning

confidence: 99%

Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

Gao

Wang

Zhou

et al. 2022

Sig Transduct Target Ther

391

189

View full text Add to dashboard Cite

In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not to ICIs, partly caused by the absence of tumor-infiltrating lymphocytes (TILs), significantly limits the application of ICIs. Converting these immune “cold” tumors into “hot” tumors that may respond to ICIs is an unsolved question in cancer immunotherapy. Since it is a general characteristic of cancers to resist apoptosis, induction of non-apoptotic regulated cell death (RCD) is emerging as a new cancer treatment strategy. Recently, several studies have revealed the interaction between non-apoptotic RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, and necroptosis exhibit synergistic antitumor immune responses while possibly exerting inhibitory effects on antitumor immune responses. Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs. This review summarizes the multilevel relationship between antitumor immunity and non-apoptotic RCD, including autophagy, ferroptosis, pyroptosis, and necroptosis, and the potential targeting application of non-apoptotic RCD to improve the efficacy of immunotherapy in malignancy.

show abstract

Section: Overview Of Necroptosismentioning

confidence: 99%

Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

Gao

Wang

Zhou

et al. 2022

Sig Transduct Target Ther

391

189

View full text Add to dashboard Cite

show abstract

“…The most highly mutated genes, such as MYC, TERT, FASLG, RIPK1, TNFSF10, TARDBP, and CDKN2A, have been well characterized in liver cancer ( 15 , 48 ), diffuse large B-cell lymphoma ( 49 ), neuroblastoma ( 50 ), and kidney renal clear cell carcinoma ( 51 , 52 ). Especially, as the three most important necroptosis-driving molecules ( 53 ), RIPK1 and MLKL were upregulated in tumors and CNV of RIPK1 revealed amplification more than depletion, while RIPK3 presented no significant alternation in genomic expression. Extrapolating from all the above results, necroptosis genes present high heterogeneity among RNA expression, CNV, and mutations in HCC samples, which shows promise in tumorigenesis and development in HCC.…”

Section: Resultsmentioning

confidence: 99%

Computational Characterizing Necroptosis Reveals Implications for Immune Infiltration and Immunotherapy of Hepatocellular Carcinoma

et al. 2022

View full text Add to dashboard Cite

Necroptosis is a programmed form of necrotic cell death in regulating cancer ontogenesis, progression, and tumor microenvironment (TME) and could drive tumor-infiltrating cells to release pro-inflammatory cytokines, incurring strong immune responses. Nowadays, there are few identified biomarkers applied in clinical immunotherapy, and it is increasingly recognized that high levels of tumor necroptosis could enhance the response to immunotherapy. However, comprehensive characterization of necroptosis associated with TME and immunotherapy in Hepatocellular carcinoma (HCC) remains unexplored. Here, we computationally characterized necroptosis landscape in HCC samples from TCGA and ICGA cohorts and stratified them into two necroptosis clusters (A or B) with significantly different characteristics in clinical prognosis, immune cell function, and TME-landscapes. Additionally, to further evaluate the necroptosis levels of each sample, we established a novel necroptosis-related gene score (NRGscore). We further investigated the TME, tumor mutational burden (TMB), clinical response to immunotherapy, and chemotherapeutic drug sensitivity of HCC subgroups stratified by the necroptosis landscapes. The NRGscore is robust and highly predictive of HCC clinical outcomes. Further analysis indicated that the high NRGscore group resembles the immune-inflamed phenotype while the low score group is analogous to the immune-exclusion or metabolism phenotype. Additionally, the high NRGscore group is more sensitive to immune checkpoint blockade-based immunotherapy, which was further validated using an external HCC cohort, metastatic melanoma cohort, and advanced urothelial cancer cohort. Besides, the NRGscore was demonstrated as a potential biomarker for chemotherapy, wherein the high NRGscore patients with more tumor stem cell composition could be more sensitive to Cisplatin, Doxorubicin, Paclitaxel-based chemotherapy, and Sorafenib therapy. Collectively, a comprehensive characterization of the necroptosis in HCC suggested its implications for predicting immune infiltration and response to immunotherapy of HCC, providing promising strategies for treatment.

show abstract

“…As a kinase, activation of RIPK3 promotes the phosphorylation of MLKL to form a RIPK3–MLKL complex (also known as a necrosome) to induce necroptosis. Activated MLKL is translocated into the cell membrane, thus forcing the cell membrane to rupture [ 30 ]. As IL-37 did not affect total MLKL protein, it is hypothesized that it is likely to regulate RIPK3 and, thus, influence the phosphorylation of MLKL.…”

Section: Discussionmentioning

confidence: 99%

IL-37 Expression in Patients with Abdominal Aortic Aneurysm and Its Role in the Necroptosis of Vascular Smooth Muscle Cells

Ding

Wang

Cai

et al. 2022

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Background. Our previous studies have shown that interleukin- (IL-) 37 plays a protective role in patients and animal models with coronary artery disease. However, the role of IL-37 in patients with abdominal aortic aneurysm (AAA), another artery disease, is yet to be elucidated. Methods and Results. AAA tissues and plasma samples were obtained from patients with or without surgical intervention. Normal renal aortic tissues were collected from kidney transplant donors. Our findings established that in AAA, IL-37 was distributed in endothelial cells, macrophages, and vascular smooth muscle cells (VSMCs) and that it was chiefly concentrated in VSMCs. Furthermore, the expression was found to be downregulated compared with that in normal artery tissues. Immunofluorescence showed that, unlike normal arteries, IL-37 was translocated to the nucleus of VSMCs in AAA. Moreover, in patients with AAA, the expressions of IL-37, IL-6, and tumor necrosis factor- (TNF-) α were increased in the plasma in comparison with the healthy controls. Correlation analysis revealed that IL-37 was positively correlated with IL-6, TNF-α, age, aneurysm diameter, and blood pressure. Furthermore, human aortic vascular smooth muscle cells (HASMCs) were stimulated with angiotensin II (AngII) in vitro to simulate smooth muscle cell (SMC) damage in AAA. A decrease in IL-37 expression and an increase in receptor-interacting serine/threonine-protein kinase 3 (RIPK3) expression were observed in HASMCs stimulated with AngII. On this basis, inhibition of RIPK3 with GSK’872 significantly attenuated necroptosis. Moreover, the necroptosis rates were significantly lowered in HASMCs treated with recombinant IL-37, whereas the rates were enhanced when the cells were depleted of the interleukin. Immunoblotting results showed that both exogenous and endogenous IL-37 could affect the expressions of RIPK3, NLRP3, and IL-1β. Also, the phosphorylation of RIPK3 and p65 was affected. Meanwhile, IL-37 promoted the transition of SMC from proliferative type to contractile type. Conclusions. The expression of IL-37 in VSMCs decreases in patients with AAA, whereas IL-37 supplementation suppresses RIPK3-mediated necroptosis and promotes the transition of VSMCs from proliferative to contractile type.

show abstract

Necroptosis-driving genesRIPK1, RIPK3andMLKL-pare associated with intratumoral CD3⁺and CD8⁺T cell density and predict prognosis in hepatocellular carcinoma

Cited by 37 publications

References 45 publications

Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

Computational Characterizing Necroptosis Reveals Implications for Immune Infiltration and Immunotherapy of Hepatocellular Carcinoma

IL-37 Expression in Patients with Abdominal Aortic Aneurysm and Its Role in the Necroptosis of Vascular Smooth Muscle Cells

Contact Info

Product

Resources

About