Autophagy blockade potentiates cancer‐associated immunosuppression through programmed death ligand‐1 upregulation in bladder cancer

Tsai, Te‐Fu; Chang, An‐Chen; Chen, Po‐Chun; Ho, Chao‐Yen; Chen, Hung‐En; Chou, Kan‐Sen; Hwang, Thomas I‐Sheng

doi:10.1002/jcp.30817

Cited by 11 publications

(7 citation statements)

References 52 publications

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“…Similarly, combined RT, mTOR and PD-1 inhibitors could enhance radiosensitivity in cervical cancer by promoting autophagy [174]. Consistently, Tsai et al indicated that autophagy blockade by inhibitors increased PD-L1 expression through the ERK and JNK signaling pathways in bladder cancer cells [175]. In contrast, other studies have shown that PD-L1 can inhibit autophagy by activating mTORC1 signaling and inhibiting mTORC2 signaling [176].…”

Section: The Dual Roles Of Autophagy In Rt Immunotherapy and Nanotech...mentioning

confidence: 88%

Nanoparticles augment the therapeutic window of RT and immunotherapy for treating cancers: pivotal role of autophagy

Wu¹,

Chen²,

Chiu³

et al. 2023

Theranostics

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Immunotherapies are now emerging as an efficient anticancer therapeutic strategy. Cancer immunotherapy utilizes the host's immune system to fight against cancer cells and has gained increasing interest due to its durable efficacy and low toxicity compared to traditional antitumor treatments, such as chemotherapy and radiotherapy (RT). Although the combination of RT and immunotherapy has drawn extensive attention in the clinical setting, the overall response rates are still low. Therefore, strategies for further improvement are urgently needed. Nanotechnology has been used in cancer immunotherapy and RT to target not only cancer cells but also the tumor microenvironment (TME), thereby helping to generate a long-term immune response. Nanomaterials can be an effective delivery system and a strong autophagy inducer, with the ability to elevate autophagy to very high levels. Interestingly, autophagy could play a critical role in optimal immune function, mediating cell-extrinsic homeostatic effects through the regulation of danger signaling in neoplastic cells under immunogenic chemotherapy and/or RT. In this review, we summarize the preclinical and clinical development of the combination of immunotherapy and RT in cancer therapy and highlight the latest progress in nanotechnology for augmenting the anticancer effects of immunotherapy and RT. The underlying mechanisms of nanomaterial-triggered autophagy in tumor cells and the TME are discussed in depth. Finally, we suggest the implications of these three strategies combined together to achieve the goal of maximizing the therapeutic advantages of cancer therapy and show recent advances in biomarkers for tumor response in the evaluation of those therapies.

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Section: The Dual Roles Of Autophagy In Rt Immunotherapy and Nanotech...mentioning

confidence: 88%

Nanoparticles augment the therapeutic window of RT and immunotherapy for treating cancers: pivotal role of autophagy

Wu¹,

Chen²,

Chiu³

et al. 2023

Theranostics

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“…Previous study has demonstrated that the expression levels of PD-L1 negatively associates with autophagic activities, and autophagy inhibition increases PD‐L1 expression leading to immune evasion in bladder cancer (Tsai et al. 2022 ). Additionally, autophagy-related genes signature has been proved to be efficient in predicting immunotherapeutic effect in bladder cancer (Cao et al.…”

Section: Discussionmentioning

confidence: 99%

Homogeneous Polyporus polysaccharide exerts anti-bladder cancer effects via autophagy induction

Luo,

Huang,

et al. 2024

Pharmaceutical Biology

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Context Polyporus polysaccharide (PPS), the leading bioactive ingredient extracted from Polyporus umbellatus (Pers.) Fr. (Polyporaceae), has been demonstrated to exert anti-bladder cancer and immunomodulatory functions in macrophages. Objective To explore the effects of homogeneous Polyporus polysaccharide (HPP) on the proliferation and autophagy of bladder cancer cells co‐cultured with macrophages. Materials and methods MB49 bladder cancer cells and RAW264.7 macrophages were co-cultured with or without HPP intervention (50, 100, or 200 μg/mL) for 24 h. The cell counting kit-8 (CCK-8) assay and 5-ethynyl-2″-deoxyuridine (EdU) staining evaluated MB49 cell proliferation. Monodansylcadaverine (MDC) staining and transmission electron microscopy (TEM) observed autophagosomes. Western blotting detected the expression levels of autophagy-related proteins and PI3K/Akt/mTOR pathway proteins. Results HPP inhibited the proliferation of MB49 cells co-cultured with RAW264.7 cells but not MB49 cells alone. HPP altered the expression of autophagy-related proteins and promoted the formation of autophagosomes in MB49 cells in the co-culture system. Autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) not only antagonized HPP-induced autophagy but also attenuated the inhibitory effects of HPP on MB49 cell proliferation in the co-culture system. HPP or RAW264.7 alone was not sufficient to induce autophagy in MB49 cells. In addition, HPP suppressed the protein expression of the PI3K/Akt/mTOR pathway in MB49 cells in the co-culture system. Discussion and conclusions HPP induced bladder cancer cell autophagy by regulating macrophages in the co-culture system, resulting in the inhibition of cancer cell proliferation. The PI3K/Akt/mTOR pathway was involved in HPP-induced autophagy in the co-culture system.

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“…MiR-34a also negative regulates EMT activity by targeting EMT-transcription factors ZEB1 (41), Snail (42) and Twist (43) in various cancers, showing the broad potency of miR-34a as a tumor suppressor. Moreover, miR-34a has been reported to be involved in tumor-mediated immunosuppression (44,45). Mechanistically, the overexpression of miR-34a in cells from acute myeloid leukemia blocks PD-L1 surface expression, which interrupts PD-L1-specific T cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressive functions of hsa‑miR‑34a on cell cycle, migration and protective autophagy in bladder cancer

Hwang¹,

Cuiu²,

Chen³

et al. 2023

Int J Oncol

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Bladder cancer (BC) cells exhibit a high basal level of autophagy activity, which contributes to the development of a protective mechanism for cellular survival against current treatments. Hsa-microRNA-34a (miR-34a) presents anti-tumor function in several types of cancer. However, the functional mechanism of miR-34a in regulating tumor aggressiveness and protective autophagy of BC remains largely unknown. First, transfected BC cells with miR-34a mimic exhibited LC3-II and p62 accumulation through immunofluorescence staining. It was demonstrated that syntaxin 17 (STX17), which is required for autophagosome-lysosome fusion, was downregulated upon miR-34a mimic treatment. Mechanistically, miR-34a reduced the expression of STX17 proteins that directly bind on STX17 3'-untranslated regions and thus suppressed STX17 mRNA translation to eventually inhibit protective autophagy in BC. Cell viability and colony formation assays revealed that overexpression of miR-34a in BC cells enhances the chemosensitivity of cisplatin, doxorubicin, epirubicin and mitomycin C. Furthermore, miR-34a inhibited cell proliferation and triggered G0/G1 cell cycle arrest by inhibiting cyclin D1 and cyclin E2 protein expression. Moreover, miR-34a suppressed cell motility through the downregulation of epithelial-mesenchymal transition. In summary, miR-34a inhibits cell proliferation, motility and autophagy activity in BC, which can benefit BC treatment.

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Autophagy blockade potentiates cancer‐associated immunosuppression through programmed death ligand‐1 upregulation in bladder cancer

Cited by 11 publications

References 52 publications

Nanoparticles augment the therapeutic window of RT and immunotherapy for treating cancers: pivotal role of autophagy

Nanoparticles augment the therapeutic window of RT and immunotherapy for treating cancers: pivotal role of autophagy

Homogeneous Polyporus polysaccharide exerts anti-bladder cancer effects via autophagy induction

Tumor suppressive functions of hsa‑miR‑34a on cell cycle, migration and protective autophagy in bladder cancer

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