Programmed cell death in tumor immunity: mechanistic insights and clinical implications
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PROVIDER: S-EPMC10811021 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:The demise of cells in various ways enables the body to clear unwanted cells. Studies over the years revealed distinctive molecular mechanisms and functional consequences of several key cell death pathways. Currently, the most intensively investigated programmed cell death (PCD) includes apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, which has been discovered to play crucial roles in modulating the immunosuppressive tumor microenvironment (TME) and determining clinical outcomes of the cancer therapeutic approaches. PCD can play dual roles, either pro-tumor or anti-tumor, partly depending on the intracellular contents released during the process. PCD also regulates the enrichment of effector or regulatory immune cells, thus participating in fine-tuning the anti-tumor immunity in the TME. In this review, we focused primarily on apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, discussed the released molecular messengers participating in regulating their intricate crosstalk with the immune response in the TME, and explored the immunological consequence of PCD and its implications in future cancer therapy developments.
| S-EPMC9005769 | biostudies-literature
Project description: Not available
| S-EPMC10850370 | biostudies-literature
Project description:Programmed Cell Death-1 (PD-1) is an inhibitory immune receptor, which plays critical roles in T cell co-inhibition and exhaustion upon binding to its ligands PD-L1 and PD-L2. We report the crystal structure of the human PD-1 ectodomain and the mapping of the PD-1 binding interface. Mutagenesis studies confirmed the crystallographic interface, and resulted in mutant PD-1 receptors with altered affinity and ligand-specificity. In particular, a high-affinity mutant PD-1 (HA PD-1) exhibited 45 and 30-fold increase in binding to PD-L1 and PD-L2, respectively, due to slower dissociation rates. This mutant (A132L) was used to engineer a soluble chimeric Ig fusion protein for cell-based and in vivo studies. HA PD-1 Ig showed enhanced binding to human dendritic cells, and increased T cell proliferation and cytokine production in a mixed lymphocyte reaction (MLR) assay. Moreover, in an experimental model of murine Lewis lung carcinoma, HA PD-1 Ig treatment synergized with radiation therapy to decrease local and metastatic tumor burden, as well as in the establishment of immunological memory responses. Our studies highlight the value of structural considerations in guiding the design of a high-affinity chimeric PD-1 Ig fusion protein with robust immune modulatory properties, and underscore the power of combination therapies to selectively manipulate the PD-1 pathway for tumor immunotherapy.
| S-EPMC5360572 | biostudies-literature
Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is a deadly type of esophageal cancer. Programmed cell death (PCD) is an important pathway of cellular self-extermination and is closely involved in cancer progression. A detailed study of its mechanism may contribute to ESCC treatment.MethodsWe obtained expression profiling data of ESCC patients from public databases and genes related to 12 types of PCD from previous studies. Hub genes in ESCC were screened from PCD-related genes applying differential expression analysis, machine learning analysis, linear support vector machine (SVM), random forest and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. In addition, based on the HTFtarget and TargetScan databases, transcription factors (TFs) and miRNAs interacting with the hub genes were selected. The relationship between hub genes and immune cells were analyzed using the CIBERSORT algorithm. Finally, to verify the potential impact of the screened hub genes on ESCC occurrence and development, a series of in vitro cell experiments were conducted.ResultsWe screened 149 PCD-related DEGs, of which five DEGs (INHBA, LRRK2, HSP90AA1, HSPB8, and EIF2AK2) were identified as the hub genes of ESCC. The area under the curve (AUC) of receiver operating characteristic (ROC) curve of the integrated model developed using the hub genes reached 0.997, showing a noticeably high diagnostic accuracy. The number of TFs and miRNAs regulating hub genes was 105 and 22, respectively. INHBA, HSP90AA1 and EIF2AK2 were overexpressed in cancer tissues and cells of ESCC. Notably, INHBA knockdown suppressed ECSS cell migration and invasion and altered the expression of important apoptotic and survival proteins.ConclusionThis study identified significant molecules with promising accuracy for the diagnosis of ESCC, which may provide a new perspective and experimental basis for ESCC research.
| S-EPMC11246021 | biostudies-literature
Project description:Programmed cell death (PCD) is a crucial process for plant innate immunity and development. In plant innate immunity, PCD is believed to prevent the spread of pathogens from the infection site. Although proper control of PCD is important for plant fitness, we have limited understanding of the molecular mechanisms regulating plant PCD. Plant innate immunity triggered by recognition of effectors (effector-triggered immunity, ETI) is often associated with PCD. However pattern-triggered immunity (PTI), which is triggered by recognition of elicitors called microbe-associated molecular patterns (MAMPs), is not. Therefore we hypothesized that PTI might suppress PCD. Here we report that PCD triggered by the mycotoxin fumonisin B1 (FB1) can be suppressed by PTI in Arabidopsis. FB1-triggered cell death was suppressed by treatment with the MAMPs flg22 (a part of bacterial flagellin) or elf18 (a part of the bacterial elongation factor EF-Tu) but not chitin (a component of fungal cell walls). Although plant hormone signaling is associated with PCD and PTI, both FB1-triggered cell death and suppression of cell death by flg22 treatment were still observed in mutants deficient in jasmonic acid (JA), ethylene (ET) and salicylic acid (SA) signaling. The MAP kinases MPK3 and MPK6 are transiently activated and inactivated within one hour during PTI. We found that FB1 activated MPK3 and MPK6 about 36-48 hours after treatment. Interestingly, this late activation was attenuated by flg22 treatment. These results suggest that PTI suppression of FB1-triggered cell death may involve suppression of MPK3/MPK6 signaling but does not require JA/ET/SA signaling.
| S-EPMC3613394 | biostudies-literature
Project description:Tumor immunotherapy, especially that involving programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive checkpoint inhibitors, has become an important part of tumor treatment strategy in the past decade. Blocking PD-1/PD-L1 signaling pathway can reduce the inhibitory effect of PD-1 pathway on T cells, promote the anti-tumor activity of activated T cells, and prolong the remission period of tumor. While PD-1/PD-L1 immunotherapy is effective in the treatment of solid malignant tumors, it also has shortcomings, due to the complexity of the tumor microenvironment (TME). Regulatory T cells (Tregs) and T helper 17 (Th17) cells play an important role in the TME and are closely related to the occurrence and development of tumors. Tregs can inhibit the anti-tumor immune effect, while Th17 cells play a dual role in tumor immunity, which not only promotes tumorigenesis but also promotes anti-tumor immunity. In the occurrence and development of tumor, PD-1/PD-L1 pathway, Tregs and Th17 cells are interrelated. However, the complicated relationship between the PD-1/PD-L1 pathway, Tregs, and Th17 cells has not been fully clarified. Here, we summarize the immunoregulation mechanisms and discuss the crosstalk between the PD-1/PD-L1 pathway, Tregs, and Th17 cells, with the aim of providing novel insights for future cancer treatment.
| S-EPMC7729304 | biostudies-literature
Project description:PurposeNovel cancer immunotherapies, called immune checkpoint inhibitors, have demonstrated clinical efficacy in the treatment of squamous cell carcinomas of the head and neck. Tissue expression of programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 ligand 2 (PD-L2) has been shown to predict tumor response to these drugs. We examine the expression of prognostic immune biomarkers, PD-L1 and PD-L2, in invasive ocular surface squamous neoplasia.DesignRetrospective case series.MethodsEighteen cases of ocular surface or ocular adnexal invasive squamous cell carcinomas were identified in pathology case files of the Massachusetts General Hospital/Massachusetts Eye and Ear Infirmary and at the Wills Eye Hospital accessioned between January 1, 2014 and January 1, 2017. Immunohistochemical staining for PD-L1, PD-L2, CD8, and p16 was performed and graded in a standardized fashion.ResultsPD-L1 and PD-L2 were expressed on tumor cells to varying degrees, and also on some stromal cells and endothelial cells. Stromal and endothelial cell expression was also seen in control conjunctival specimens. Tumor expression of PD-L1 and PD-L2 was present on the cell membranes. All 18 (100%) of the tumors expressed PD-L1: 7 (39%) expressed a high level, 3 (17%) expressed a medium level, and 8 (44%) expressed a low level. Only 9 (50%) tumors expressed PD-L2 and it was at a low level. The expression of PD-L1 in tumor cells correlated with the presence of CD8-positive cytotoxic T lymphocytes among tumor cells (P < .01) and with the presence of CD8-positive cells in the surrounding stroma (P = .04).ConclusionsA subset of ocular invasive conjunctival squamous carcinomas express high levels of PD-L1 and CD8 and therefore may respond therapeutically to immune checkpoint inhibition.
| S-EPMC7456462 | biostudies-literature
Project description:ObjectiveWe aim to analyse sex-specific differences in aortic valves (AVs) and valve interstitial cells (VICs) from aortic stenosis (AS) patients.Approach and results238 patients with severe AS undergoing surgical valve replacement were recruited. Two hundred and two AVs (39.1% women) were used for ex vivo analyses and 36 AVs (33.3% women) for in vitro experiments. AVs from men presented increased levels of the inflammatory molecules interleukin (IL)-1β, IL-6, Rantes, and CD45. Oxidative stress (eNOS, myeloperoxidase, malondialdehyde and nitrotyrosine) was upregulated in male AVs. Concerning fibrosis, similar levels of collagen type I, decreased levels of collagen type III and enhanced fibronectin, active Lox-1 and syndecan-1 expressions were found in AVs from men compared with women. Extracellular matrix (ECM) remodeling was characterized by reduced metalloproteinase-1 and 9 expression and increased tissue inhibitor of metalloproteinase-2 expression in male AVs. Importantly, osteogenic markers (bone morphogenetic protein-9, Rank-L, osteopontin, periostin, osteocalcin and Sox-9) and apoptosis (Bax, Caspase 3, p53, and PARP1) were enhanced in AVs from men as compared to women. Isolated male VICs presented higher myofibroblast-like phenotype than female VICs. Male VICs exhibited increased inflammatory, oxidative stress, fibrotic, apoptosis and osteogenic differentiation markers.ConclusionsOur results suggest that the mechanisms driving the pathogenesis of AS could be different in men and women. Male AVs and isolated VICs presented more inflammation, oxidative stress, ECM remodeling and calcification as compared to those from women. A better knowledge of the pathophysiological pathways in AVs and VICs will allow the development of sex-specific options for the treatment of AS.
| S-EPMC8907577 | biostudies-literature
Project description:BackgroundAlthough it is a crucial cellular process required for both normal development and to face stress conditions, the control of programmed cell death in plants is not fully understood. We previously reported the isolation of ATXR5 and ATXR6, two PCNA-binding proteins that could be involved in the regulation of cell cycle or cell death. A yeast two-hybrid screen using ATXR5 as bait captured AtIPS1, an enzyme which catalyses the committed step of myo-inositol (MI) biosynthesis. atips1 mutants form spontaneous lesions on leaves, raising the possibility that MI metabolism may play a role in the control of PCD in plants. In this work, we have characterised atips1 mutants to gain insight regarding the role of MI in PCD regulation.Methodology/principal findings- lesion formation in atips1 mutants depends of light intensity, is due to PCD as evidenced by TUNEL labelling of nuclei, and is regulated by phytohormones such as salicylic acid - MI and galactinol are the only metabolites whose accumulation is significantly reduced in the mutant, and supplementation of the mutant with these compounds is sufficient to prevent PCD - the transcriptome profile of the mutant is extremely similar to that of lesion mimic mutants such as cpr5, or wild-type plants infected with pathogens.Conclusion/significanceTaken together, our results provide strong evidence for the role of MI or MI derivatives in the regulation of PCD. Interestingly, there are three isoforms of IPS in Arabidopsis, but AtIPS1 is the only one harbouring a nuclear localisation sequence, suggesting that nuclear pools of MI may play a specific role in PCD regulation and opening new research prospects regarding the role of MI in the prevention of tumorigenesis. Nevertheless, the significance of the interaction between AtIPS1 and ATXR5 remains to be established.
| S-EPMC2754662 | biostudies-literature
Project description:Programmed cell death (PCD) initiated at the pathogen-infected sites during the plant innate immune response is thought to prevent the development of disease. Here, we describe the identification and characterization of an ER-localized type IIB Ca(2+)-ATPase (NbCA1) that function as a regulator of PCD. Silencing of NbCA1 accelerates viral immune receptor N- and fungal-immune receptor Cf9-mediated PCD, as well as non-host pathogen Pseudomonas syringae pv. tomato DC3000 and the general elicitor cryptogein-induced cell death. The accelerated PCD rescues loss-of-resistance phenotype of Rar1, HSP90-silenced plants, but not SGT1-silenced plants. Using a genetically encoded calcium sensor, we show that downregulation of NbCA1 results in the modulation of intracellular calcium signalling in response to cryptogein elicitor. We further show that NbCAM1 and NbrbohB function as downstream calcium decoders in N-immune receptor-mediated PCD. Our results indicate that ER-Ca(2+)-ATPase is a component of the calcium efflux pathway that controls PCD during an innate immune response.
| S-EPMC2837167 | biostudies-literature