Prodrug‐Based Versatile Nanomedicine for Enhancing Cancer Immunotherapy by Increasing Immunogenic Cell Death

Bai, Shuang; Yang, Leilei; Wang, Yajun; Tian, Ziqiang; Fu, Liang; Yang, Shao‐Chen; Wan, Shu-Yen; Wang, Shuo; Jia, Die; Li, Baosheng; Xue, Peng; Kang, Yuejun; Sun, Zhi‐Jun; Xu, Zhigang

doi:10.1002/smll.202000214

Cited by 78 publications

(34 citation statements)

References 54 publications

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“…SCC7 cells were seeded into 24-well plates, cultured for 24 h, fixed with 4% paraformaldehyde, permeated with 0.5% Triton X-100, and blocked with 5% bovine serum albumin as previously described (Bai et al 2020). Cells were then incubated with an anti-HMGB1 antibody (HMGB1, 6893; Cell Signaling Technology) at 4°C overnight, and cells were then incubated with the corresponding fluorescent secondary antibody (Abbkine).…”

Section: Methodsmentioning

confidence: 99%

GSDME Is Related to Prognosis and Response to Chemotherapy in Oral Cancer

Wang

Zhang

et al. 2022

J Dent Res

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Gasdermin E (GSDME), as the major executive protein of pyroptosis, has been considered to be linked to antitumor immunity in recent years. However, the role of GSDME in oral squamous cell carcinoma (OSCC) remains to be elucidated. Here, by using a human OSCC tissue microarray, human OSCC tissue, and Tgfbr1/ Pten conditional knockout mice, we found that GSDME was strongly expressed in OSCC and that GSDME expression in primary tumors was higher than that in metastatic lymph nodes. In addition, GSDME expression in OSCC was positively related to better prognosis. Moreover, GSDME-mediated pyroptosis occurred upon stimulation with chemotherapy drugs, and functional knockdown of GSDME attenuated the cisplatin-induced antitumor effect. Consistent with these results, bioinformatic analysis indicated that GSDME expression was positively correlated with the sensitivity of a number of antitumor drugs approved by the US Food and Drug Administration. Inhibition of GSDME expression by small interfering RNA in SCC7 cells significantly increased the expression of the cancer stem cell markers, CD44 and ALDH1. Furthermore, multiplexed immunohistochemistry and flow cytometry indicated that the expression of GSDME positively correlated with tumor-infiltrating CD8+ T cells, granzyme B, and M1 phenotype macrophages. Collectively, these findings demonstrated that GSDME is a potential positive prognostic factor of OSCC, and GSDME-mediated pyroptosis induced by chemotherapy plays a role in antitumor response.

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Section: Methodsmentioning

confidence: 99%

GSDME Is Related to Prognosis and Response to Chemotherapy in Oral Cancer

Wang

Zhang

et al. 2022

J Dent Res

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“…[9b] Thep roportion of CD8 + Tc ells (CD3 + CD8 + T lymphocytes) and activated CD8 + Tcells (CD3 + CD8 + CD38 + Tl ymphocytes) in the tumors and spleens of the mice were quantified on day 16. [44] As shown in Figure 3F and Ga nd Table S2 and Figure S32,33, in the Ir1 group 86.85 %o fthe tumor cells were activated CD8 + Tc ells,a ppreciably higher than that in the control group (60.60 %) and the CDDP group (68.63 %). Similarly,the percentage of activated CD8 + Tcells in the Ir1 group was significantly higher than that of the control group and CDDP group in the spleens of the mice ( Figure S34).…”

Section: Angewandte Chemiementioning

confidence: 86%

An ER‐Targeting Iridium(III) Complex That Induces Immunogenic Cell Death in Non‐Small‐Cell Lung Cancer

et al. 2021

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Immunogenic cell death (ICD) is a vital component of therapeutically induced anti‐tumor immunity. An iridium(III) complex (Ir1), containing an N,N‐bis(2‐chloroethyl)‐azane derivate, as an endoplasmic reticulum‐localized ICD inducer for non‐small cell lung cancer (NSCLC) is reported. The characteristic discharge of damage‐associated molecular patterns (DAMPs), that is, cell surface exposure of calreticulin (CRT), extracellular exclusion of high mobility group box 1 (HMGB1), and ATP, were generated by Ir1 in A549 lung cancer cells, accompanied by an increase in endoplasmic reticulum stress and reactive oxygen species (ROS). The vaccination of immunocompetent mice with Ir1‐treated dying cells elicited an antitumor CD8+ T cell response and Foxp3+ T cell depletion, which eventually resulted in long‐acting anti‐tumor immunity by the activation of ICD in lung cancer cells. Ir1 is the first Ir‐based complex that is capable of developing an immunomodulatory response by immunogenic cell death.

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“…The 3D MCS of B16F10 cell model was established as described in the previous report. [ 42 ] Briefly, each well of a 96‐well plate was spread with a mixture containing 50 µL of 2% low melting‐temperature agarose, 150 µL of fresh medium and ≈2000 cells. The cells were treated with fresh medium containing AOZNs@Cy7 for 4, 8, and 24 h after pelleting.…”

Section: Methodsmentioning

confidence: 99%

Inspired Epigenetic Modulation Synergy with Adenosine Inhibition Elicits Pyroptosis and Potentiates Cancer Immunotherapy

Xiong

Wang

et al. 2021

Adv Funct Materials

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Overcoming innate or adaptive resistance to immune checkpoint inhibitor therapy in solid tumors with limited T‐cell responses remains challenging. Increasing evidence has indicated that epigenetic alterations, especially overexpression of DNA methyltransferase and immunosuppressive adenosine, are major obstacles to T cell activation. Here, a tumor microenvironment (TME) inspired prodrug nanomicelle (AOZN) composed of the epigenetic modulator γ‐oryzanol (Orz), the adenosine inhibitor α, β‐methylene adenosine 5′ diphosphate (AMPCP), and GSH‐activable crosslinker, is rationally designed. High glutathione redox triggers Orz and AMPCP release in the TME. The released Orz act as a DNA methyltransferases inhibitor to upregulate gasdermin D (GSDMD) expression and AMPCP converted procaspase‐1 into active caspase‐1 by increasing ATP levels. Active caspase‐1 elicited GSDMD cleavage and induced pyroptosis in tumor cells. Furthermore, it is demonstrated that Orz and AMPCP likely have a synergistic effect in combating the immunosuppressive TME. Moreover, Orz enhances programmed death‐ligand 1 (PD‐L1) expression and sensitize tumors to anti‐PD‐L1 therapy. Thus, the AOZNs nano‐formulation drastically improves the hydrophobic properties of Orz with advantages of safe, affordable, readily available, and efficiency in regressing tumor growth, enhancing PD‐L1 responsive rate and prolonging survival of the B16F10 melanoma‐bearing mouse model. As a result, AOZNs provides a promising strategy for enhancing cancer immunotherapy.

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Prodrug‐Based Versatile Nanomedicine for Enhancing Cancer Immunotherapy by Increasing Immunogenic Cell Death

Cited by 78 publications

References 54 publications

GSDME Is Related to Prognosis and Response to Chemotherapy in Oral Cancer

GSDME Is Related to Prognosis and Response to Chemotherapy in Oral Cancer

An ER‐Targeting Iridium(III) Complex That Induces Immunogenic Cell Death in Non‐Small‐Cell Lung Cancer

Inspired Epigenetic Modulation Synergy with Adenosine Inhibition Elicits Pyroptosis and Potentiates Cancer Immunotherapy

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