Multifaceted roles of PD-1 in tumorigenesis: From immune checkpoint to tumor cell-intrinsic function.

Programmed cell death 1 (PD-1), a key immune checkpoint receptor, has been extensively studied for its role in regulating immune responses in cancer. However, recent research has unveiled a complex and dual role for PD-1 in tumorigenesis. While PD-1 is traditionally associated with immune cells, this article explores its expression in various cancer cells and its impact on cancer progression. PD-1's functions extend beyond immune regulation, as it has been found to both promote and suppress tumor growth, depending on the cancer type. These findings have significant implications for the future of cancer treatment and our understanding of the immune response in the context of cancer. This article calls for further research into the multifaceted roles of PD-1 to optimize its therapeutic potential and improve patient outcomes in the fight against cancer.

Ferroptosis is an effective strategy for cancer therapy.

Ferroptosis is a form of intracellular iron-dependent cell death that differs from necrosis, autophagy and apoptosis. Intracellular iron mediates Fenton reaction resulting in lipid peroxidation production, which in turn promotes cell death. Although cancer cell exhibit's ability to escape ferroptosis by multiple pathways such as SLC7A11, GPX4, induction of ferroptosis could inhibit cancer cell proliferation, migration and invasion. In tumor microenvironment, ferroptosis could affect immune cell (T cells, macrophages etc.) activity, which in turn regulates tumor immune escape. In addition, ferroptosis in cancer cells could activate immune cell activity by antigen processing and presentation. Therefore, ferroptosis could be an effective strategy for cancer therapy such as chemotherapy, radiotherapy, and immunotherapy. In this paper, we reviewed the role of ferroptosis on tumor progression and therapy, which may provide a strategy for cancer treatment.

GSK0660 enhances antitumor immunotherapy by reducing PD-L1 expression.

Blockade of PD-1/PD-L1 immune checkpoint is wildly used for multiple types of cancer treatment, while the low response rate for patients is still completely unknown. As nuclear hormone receptor, PPARδ (peroxisome-proliferator-activated receptor) regulates cell proliferation, inflammation, and tumor progression, while the effect of PPARδ on tumor immune escape is still unclear. Here we found that PPARδ antagonist GSK0660 significantly reduced colon cancer cell PD-L1 protein and gene expression. Luciferase analysis showed that GSK0660 decreased PD-L1 gene transcription activity. Moreover, reduced PD-L1 expression in colon cancer cells led to increased T cell activity. Further analysis showed that GSK0660 decreased PD-L1 expression in a PPARδ dependent manner. Implanted tumor model analysis showed that GSK0660 inhibited tumor immune escape and the combined PD-1 antibody with GSK0660 effectively enhanced colorectal cancer immunotherapy. These findings suggest that GSK0660 treatment could be an effective strategy for cancer immunotherapy.

Dual function of activated PPARγ by ligands on tumor growth and immunotherapy.

As one of the peroxisome-proliferator-activated receptors (PPARs) members, PPARγ is a ligand binding and activated nuclear hormone receptor, which is an important regulator in metabolism, proliferation, tumor progression, and immune response. Increased evidence suggests that activation of PPARγ in response to ligands inhibits multiple types of cancer proliferation, metastasis, and tumor growth and induces cell apoptosis including breast cancer, colon cancer, lung cancer, and bladder cancer. Conversely, some reports suggest that activation of PPARγ is associated with tumor growth. In addition to regulating tumor progression, PPARγ could promote or inhibit tumor immunotherapy by affecting macrophage differentiation or T cell activity. These controversial findings may be derived from cancer cell types, conditions, and ligands, since some ligands are independent of PPARγ activity. Therefore, this review discussed the dual role of PPARγ on tumor progression and immunotherapy.

Regulation of cancer progression by CK2: an emerging therapeutic target.

Casein kinase II (CK2) is an enzyme with pleiotropic kinase activity that catalyzes the phosphorylation of lots of substrates, including STAT3, p53, JAK2, PTEN, RELA, and AKT, leading to the regulation of diabetes, cardiovascular diseases, angiogenesis, and tumor progression. CK2 is observed to have high expression in multiple types of cancer, which is associated with poor prognosis. CK2 holds significant importance in the intricate network of pathways involved in promoting cell proliferation, invasion, migration, apoptosis, and tumor growth by multiple pathways such as JAK2/STAT3, PI3K/AKT, ATF4/p21, and HSP90/Cdc37. In addition to the regulation of cancer progression, increasing evidence suggests that CK2 could regulate tumor immune responses by affecting immune cell activity in the tumor microenvironment resulting in the promotion of tumor immune escape. Therefore, inhibition of CK2 is initially proposed as a pivotal candidate for cancer treatment. In this review, we discussed the role of CK2 in cancer progression and tumor therapy.

Inhibition of CK2/ING4 Pathway Facilitates Non-Small Cell Lung Cancer Immunotherapy.

Immune cells can protect against tumor progression by killing cancer cells, while aberrant expression of the immune checkpoint protein PD-L1 (programmed death ligand 1) in cancer cells facilitates tumor immune escape and inhibits anti-tumor immunotherapy. As a serine/threonine kinase, CK2 (casein kinase 2) regulates tumor progression by multiple pathways, while it is still unclear the effect of CK2 on tumor immune escape. Here it is found that ING4 induced PD-L1 autophagic degradation and inhibites non-small cell lung cancer (NSCLC) immune escape by increasing T cell activity. However, clinical analysis suggests that high expression of CK2 correlates with low ING4 protein level in NSCLC. Further analysis shows that CK2 induce ING4-S150 phosphorylation leading to ING4 ubiquitination and degradation by JFK ubiquitin ligase. In contrast, CK2 gene knockout increases ING4 protein stability and T cell activity, subsequently, inhibites NSCLC immune escape. Furthermore, the combined CK2 inhibitor with PD-1 antibody effectively enhances antitumor immunotherapy. These findings provide a novel strategy for cancer immunotherapy.

PPARγ agonist inhibits c-Myc-mediated colorectal cancer tumor immune escape.

As a master transcription factor, c-Myc plays an important role in promoting tumor immune escape. In addition, PPARγ (peroxisome proliferator-activated receptor γ) regulates cell metabolism, inflammation, and tumor progression, while the effect of PPARγ on c-Myc-mediated tumor immune escape is still unclear. Here we found that cells treated with PPARγ agonist pioglitazone (PIOG) reduced c-Myc protein expression in a PPARγ-dependent manner. qPCR analysis showed that PIOG had no significant effect on c-Myc gene levels. Further analysis showed that PIOG decreased c-Myc protein half-life. Moreover, PIOG increased the binding of c-Myc to PPARγ, and induced c-Myc ubiquitination and degradation. Importantly, c-Myc increased PD-L1 and CD47 immune checkpoint protein expression and promoted tumor immune escape, while PIOG inhibited this event. These findings suggest that PPARγ agonist inhibited c-Myc-mediated tumor immune escape by inducing its ubiquitination and degradation.

PPARγ agonist pioglitazone enhances colorectal cancer immunotherapy by inducing PD-L1 autophagic degradation.

Blockade of PD-1/PD-L1 immune checkpoint could be an effective antitumor strategy for multiple types of cancer, but it is low response rate for colorectal cancer patients with unclear mechanism. Here we found that PPARγ agonist pioglitazone could reduce PD-L1 protein levels without effect on its gene expression. Further analysis showed that pioglitazone induced PD-L1 autophagic degradation in a PPARγ-dependent manner. Pioglitazone promoted PD-L1 translocation to lysosome by immunofluorescence analysis, which was associated with the increased binding of PPARγ to PD-L1. Moreover the combined pioglitazone with PD-1 antibody enhanced colorectal tumor immunotherapy, which was involved in reduced PD-L1 levels and increased CD8+ T cells. These findings suggest that PPARγ agonist could induce PD-L1 autophagic degradation resulting in increased colorectal tumor immunotherapy.

PPARγ inhibited tumor immune escape by inducing PD-L1 autophagic degradation.

Blockade of the programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) immune checkpoint could increase antitumor immunotherapy for multiple types of cancer, but the response rate of patients is about 10%-40%. Peroxisome proliferator activated receptor γ (PPARγ) plays an important role in regulating cell metabolism, inflammation, immunity, and cancer progression, while the mechanism of PPARγ on cancer cell immune escape is still unclear. Here we found that PPARγ expression exhibits a positive correlation with activation of T cells in non-small-cell lung cancer (NSCLC) by clinical analysis. Deficiency of PPARγ promoted immune escape of NSCLC by inhibiting T-cell activity, which was associated with increased PD-L1 protein level. Further analysis showed that PPARγ reduced PD-L1 expression independent of its transcriptional activity. PPARγ contains the microtubule-associated protein 1A/1B-light chain 3 (LC3) interacting region motif, which acts as an autophagy receptor for PPARγ binding to LC3, leading to degradation of PD-L1 in lysosomes, which in turn suppresses NSCLC tumor growth by increasing T-cell activity. These findings suggest that PPARγ inhibits the tumor immune escape of NSCLC by inducing PD-L1 autophagic degradation.

Let-7b-5p inhibits colon cancer progression by prohibiting APC ubiquitination degradation and the Wnt pathway by targeting NKD1.

Naked cuticle homolog 1 (NKD1), which is expressed at low levels in many tumors, is considered an inhibitor of the Wnt/ß-catenin pathway, but it is highly expressed in colon cancer and can promote colon cancer cell proliferation. miRNAs are involved in the occurrence and progression of many tumors. However, miRNAs that can regulate NKD1 and the mechanisms by which NKD1 regulates tumor progression remain ambiguous. This research aims to reveal the potential regulatory network of NKD1 in colon cancer. miRNA data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed by bioinformatics to screen for potential miRNAs targeting NKD1. Let-7b-5p was found to inhibit proliferation, migration, and invasion of colon cancer cells targeting NKD1. Further studies suggested that let-7b-5p can modulate Wnt signaling activity, and the nuclear accumulation of ß-catenin was significantly restrained by let-7b-5p through targeting NKD1. Moreover, NKD1 could prohibit the expression of the APC protein. Further studies manifested that NKD1 bound to APC and promoted the ubiquitination degradation of APC through restraining the expression of the deubiquitinating enzyme USP15 and blocking the combination between USP15 and APC. Functionally, NKD1 enhanced the proliferation and migration of colon cancer cells by inhibiting APC expression. This research revealed a novel mechanism by which the let-7b-5p-NKD1-APC-ß-catenin signaling pathway inhibited colon cancer cell progression.

Role of ferroptosis on tumor progression and immunotherapy.

Ferroptosis is triggered by intracellular iron leading to accumulation of lipid peroxidation consequent promotion of cell death. Cancer cell exhibits ability to evade ferroptosis by activation of antioxidant signaling pathways such as SLC7A11/GPX4 axis. In addition to transcriptional regulation on ferroptosis by NRF2, SREBP1, YAP, and p53, ferroptosis is modulated by ubiquitination or autophagic degradation. Moreover, zinc or Ca2+ could modulate ferroptosis by inducing lipid peroxidation and ferroptosis. Induction of ferroptosis enhances immune cell activity such as T cells or macrophages, which is associated with the release of DAMPs (damage-associated molecular patterns) and IFNγ. Therefore, combined immune checkpoint inhibitors with ferroptosis inducers effectively enhance antitumor immunotherapy, whereas induction of ferroptosis could impair T cell activity or survival, suggesting that rational combined therapy for cancer is essential. In this review, we discussed the regulatory role of ferroptosis on tumor progression and immunotherapy.

CD47/SIRPα pathway mediates cancer immune escape and immunotherapy.

The adaptive immune checkpoints such as PD-1(programmed death-1)/PD-L1 (programmed death-ligand 1) play an important role in cancer immunotherapy, whereas increasing evidence suggests that cancer cell evades immune surveillance by innate immune checkpoints such as SIRPα (signal-regulatory protein α)/CD47 (cluster of differentiation 47). In multiple types of cancer cells and solid tumor tissues, highly expressed CD47 protein level has been observed, which is triggered by some transcription factors including NFκB, Myc, and HIF. As a transmembrane protein, the binding of CD47 to SIRPα ligand on phagocytes results in phagocytosis resistance and cancer cell immune escape. In contrast, CD47-SIRPα interaction blockade enhances cancer cell clearance by phagocytes such as macrophages and dendritic cells (DCs) to activate an innate immune response, whereas this process could promote antigen cross-presentation by antigen present cells (APCs) leading to T cell priming, consequently, activates an adaptive antitumor immune response. In this review, we discussed the current SIRPα-CD47 axis-mediated cancer cell immune escape and immunotherapy, which could provide an effective antitumor strategy by the innate and adaptive immune response.

Role of autophagy on cancer immune escape.

Autophagy is catabolic process by degradation of intracellular components in lysosome including proteins, lipids, and mitochondria in response to nutrient deficiency or stress such as hypoxia or chemotherapy. Increasing evidence suggests that autophagy could induce immune checkpoint proteins (PD-L1, MHC-I/II) degradation of cancer cells, which play an important role in regulating cancer cell immune escape. In addition to autophagic degradation of immune checkpoint proteins, autophagy induction in immune cells (macrophages, dendritic cells) manipulates antigen presentation and T cell activity. These reports suggest that autophagy could negatively or positively regulate cancer cell immune escape by immune checkpoint protein and antigens degradation, cytokines release, antigens generation. These controversial phenomenon of autophagy on cancer cell immune evasion may be derived from different experimental context or models. In addition, autophagy maybe exhibit a role in regulating host excessive immune response. So rational combination with autophagy could enhance the efficacy of cancer immunotherapy. In this review, the current progress of autophagy on cancer immune escape is discussed. Video Abstract.

AMPK phosphorylates PPARδ to mediate its stabilization, inhibit glucose and glutamine uptake and colon tumor growth.

Peroxisome proliferator-activated receptor δ (PPARδ) is a nuclear receptor transcription factor that plays an important role in the regulation of metabolism, inflammation, and cancer. In addition, the nutrient-sensing kinase 5'AMP-activated protein kinase (AMPK) is a critical regulator of cellular energy in coordination with PPARδ. However, the molecular mechanism of the AMPK/PPARδ pathway on cancer progression is still unclear. Here, we found that activated AMPK induced PPARδ-S50 phosphorylation in cancer cells, whereas the PPARδ/S50A (nonphosphorylation mimic) mutant reversed this event. Further analysis showed that the PPARδ/S50E (phosphorylation mimic) but not the PPARδ/S50A mutant increased PPARδ protein stability, which led to reduced p62/SQSTM1-mediated degradation of misfolded PPARδ. Furthermore, PPARδ-S50 phosphorylation decreased PPARδ transcription activity and alleviated PPARδ-mediated uptake of glucose and glutamine in cancer cells. Soft agar and xenograft tumor model analysis showed that the PPARδ/S50E mutant but not the PPARδ/S50A mutant inhibited colon cancer cell proliferation and tumor growth, which was associated with inhibition of Glut1 and SLC1A5 transporter protein expression. These findings reveal a new mechanism of AMPK-induced PPARδ-S50 phosphorylation, accumulation of misfolded PPARδ protein, and inhibition of PPARδ transcription activity contributing to the suppression of colon tumor formation.

EGFR/PPARδ/HSP90 pathway mediates cancer cell metabolism and chemoresistance.

Epidermal growth factor receptor (EGFR) induces peroxisome-proliferator-activated receptor-δ (PPARδ)-Y108 phosphorylation, while it is unclear the effect of phosphorylation of PPARδ on cancer cell metabolism. Here we found that EGF treatment increased its protein stability by inhibiting its lysosomal dependent degradation, which was reduced by gefitinib (EGFR inhibitor) treatment. PPARδ-Y108 phosphorylation in response to EGF recruited HSP90 (heat shock protein 90) to PPARδ resulting in increased PPARδ stability. In addition, PPARδ-Y108 phosphorylation promoted cancer cell metabolism, proliferation, and chemoresistance. Therefore, this study revealed a novel molecular mechanism of EGFR/HSP90/PPARδ pathway-mediated cancer cell metabolism, proliferation, and chemoresistance, which provides a strategy for cancer treatment.

PD-L1 degradation pathway and immunotherapy for cancer.

Programmed death ligand 1 (PD-L1, CD274) is an essential immune checkpoint protein that binds to programmed death 1 (PD-1) on T-lymphocytes. T cell plays a critical role in killing cancer cells while the cancer cell exhibits immune escape by the expression of PD-L1. The binding of PD-L1 to PD-1 inhibits T cell proliferation and activity, leading to tumor immunosuppression. Increasing evidence shows that PD-L1 protein undergoes degradation in proteasomes or lysosomes by multiple pathways, leading to enhanced immunotherapy for cancer. Although some specific drugs induce PD-L1 degradation and increase antitumor activity, the combination of these drugs with PD-L1/PD-1 blockade significantly enhances cancer immunotherapy. In this review, we have discussed the interaction of PD-L1 degradation with cancer immunotherapy.

DPEP1 promotes the proliferation of colon cancer cells via the DPEP1/MYC feedback loop regulation.

DPEP1 is highly expressed in the colorectal carcinoma tissues and colon cancer cells. However, the function and underlying mechanism of DPEP1 in the colon cancer cells are still poorly understood. Here, we found that transcription factor MYC could occupy on the DPEP1 promoter and activate its activities, and DPEP1 was up-regulated by MYC proteins in mRNA and protein levels in a dose-dependent manner in colon cancer cells. The expression levels of DPEP1 were positively correlated with that of MYC in colorectal tumor tissues. Moreover, Laser confocal images and Co-immunoprecipitation (Co-IP) revealed that DPEP1 and MYC proteins could bind to each other in the colon cancer cells. In turn, DPEP1 could enhance the stability of MYC proteins by extending the half-life of MYC proteins in colon cancer cells. Thus, DPEP1 and MYC proteins might form a positive feedback loop to maintain their high expression levels in colon cancer cells. In function, the MTT, EdU, Clone Formation assays and xenograft tumors assays demonstrated that DPEP1 could boost the proliferation of colon cancer cells through the DPEP1/MYC positive feedback loop in vitro and in vivo. Theoretically, DPEP1 may serve as a colon cancer biomarker and a novel target of colorectal carcinogenesis therapy.

PPARδ is a regulator of autophagy by its phosphorylation.

In response to nutrient deficiency, autophagy degrades cytoplasmic materials and organelles in lysosomes, which is nutrient recycling, whereas activation of EGFR mediates autophagy suppression in response to growth factors. It is unclear whether PPARδ could be the regulator of autophagy in response to active EGFR. Here we found that EGFR induced PPARδ phosphorylation at tyrosine-108 leading to increased binding of LC3 to PPARδ by its LIR (LC3 interacting region) motif, consequently, inhibited autophagic flux. Conversely, EGFR inhibitor treatment reversed this event. Furthermore, EGFR-mediated PPARδ phosphorylation at tyrosine-108 led to autophagy inhibition and tumor growth. These findings suggest that PPARδ serves as a regulator of autophagy by its phosphorylation.

Identification of potential novel biomarkers to differentiate malignant thyroid nodules with cytological indeterminate.

BACKGROUND: The fine-needle aspiration (FNA) biopsy was broadly applied to clinical diagnostics evaluation for thyroid carcinomas nodule, while companioning with higher uncertainty rate (15~30%) to identify malignancy for cytological indeterminate cases. It is requirement to discover novel molecular biomarkers to differentiate malignant thyroid nodule more precise. METHODS: We employed weighted gene co-expression network analysis (WGCNA) to discover genes significantly associated with malignant histopathology for cytological indeterminate nodules. In addition, identified significantly genes were validated through another independently investigations of thyroid carcinomas patient's samples via cBioportal and Geipa. The key function pathways of significant genes involving were blast through GenClip. RESULTS: Twenty-four signature genes were identified significantly related to thyroid nodules malignancy. Furthermore, five novel genes with missense mutation, FN1 (R534P), PROS1((K200I), (Q571K)), SCEL (T320S), SLC34A2(T688M) and TENM1 (S1131F), were highlighted as potential biomarkers to rule out nodules malignancy. It was identified that the key functional pathways involving in thyroid carcinomas. CONCLUSION: These results will be helpful to better understand the mechanism of thyroid nodules malignant transformation and characterize the potentially biomarkers for thyroid carcinomas early diagnostics.

PPARα agonist alleviates tumor growth and chemo-resistance associated with the inhibition of glucose metabolic pathway.

As a nuclear receptor, peroxisome-proliferator-activated receptor α (PPARα) plays a critical role in regulation of metabolism and cancer, while the effect of PPARα agonist on cancer cell glucose metabolism-linked tumor growth is still unclear. Here we found that PPARα agonist (Wy14,643) decreased Glut1 (Glucose transporter 1) gene and protein expressions of colorectal cancer cell lines in response to normoxia or hypoxia. Dual-luciferase analysis showed that Wy14,643 inhibited Glut1 transcription activity. Importantly, ChIP-qPCR analysis showed that Wy14,643 increased the binding of PPARα to Glut1 promoter region. Wy14,643 suppressed Glut1 transcription activity resulting in reduced influx of glucose in cancer cells in response to normoxia or hypoxia. Further analysis showed that Wy14,643-mediated inhibition of tumor growth and chemo-resistance was associated with inhibition of mTOR pathway. Taken together, PPARα agonist Wy14,643 suppressed Glut1 transcription activity, glucose uptake and mTOR pathway in colorectal cancer cells, which was involved in reduced tumor growth and chemo-resistance. These findings provided a novel therapy strategy for cancer progression.