Novel calreticulin-nanoparticle in combination with focused ultrasound induces immunogenic cell death in melanoma to enhance antitumor immunity

Sethuraman, Sri Nandhini; Singh, Mohit Pratap; Patil, Girish; Li, Shitao; Fiering, Steven; Hoopes, P. Jack; Guha, Chandan; Malayer, Jerry R.; Ranjan, Ashish

doi:10.7150/thno.42243

Cited by 52 publications

(53 citation statements)

References 64 publications

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“…Investigation into the mechanisms behind the trigger for this anti-tumor immunity remains an interesting pursuit. Notably, recent studies have found that certain chemotherapies 38 , PTT 39 , photodynamic therapy 40 - 42 and other treatments 43 - 45 can initiate an antitumor immune response by inducing tumor cells to undergo immunogenic cell death (ICD). Furthermore, cancer cells undergoing ICD can release immunostimulatory damage-associated molecular patterns (DAMPs) that act as potent danger signals, including calreticulin (CRT) exposure on the surface of tumor cells, release of large amounts of high-mobility group box 1 (HMGB1) or extracellular secretion of adenosine triphosphate (ATP).…”

Section: Resultsmentioning

confidence: 99%

ZnO-based multifunctional nanocomposites to inhibit progression and metastasis of melanoma by eliciting antitumor immunity via immunogenic cell death

Zhang

Guo²,

Liu³

et al. 2020

Theranostics

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Rationale: The development of a highly effective and tumor-specific therapeutic strategy, which can act against the primary tumor and also condition the host immune system to eliminate distant tumors, remains a clinical challenge. Methods: Herein, we demonstrate a facile yet versatile ZnO-capping and Doxorubicin (DOX)-loaded multifunctional nanocomposite (AuNP@mSiO 2 @DOX-ZnO) that integrates photothermal properties of gold nanoparticles (NPs), pH-responsive properties and preferential selectivity to tumor cells of ZnO QDs and chemotherapeutic agent into a single NP. The photothermal performance, pH-triggered release and preferential phagocytic ability were assessed. The induced anti-tumor immunity was determined by analyzing immune cell profile in tumor in vivo and molecular mechanism were identified by detecting expression of immunogenic cell death (ICD) markers in vitro . Moreover, mice models of unilateral and bilateral subcutaneous melanoma and lung metastasis were established to evaluate the antitumor effects. Results: As an efficient drug carrier, ZnO-capped NPs guarantee a high DOX payload and an in vitro , efficient release of at pH 5.0. In murine melanoma models, the nanocomposite can significantly inhibit tumor growth for a short period upon low-power laser irradiation. Importantly, ZnO NPs not only demonstrate preferential selectivity for melanoma cells but can also induce ICD. Meanwhile, AuNP@mSiO 2 -based photothermal therapy (PTT) and DOX are directly cytotoxic towards cancer cells and demonstrate an elevated ICD effect. The induced ICD promotes maturation of dendritic cells, further stimulating the infiltration of effector T cells into tumor sites, preventing tumor growth and distant lung metastases. Conclusions: This study highlights the novel mechanism of ZnO-triggered anti-tumor immunity via inducing ICD. Additionally, we shed light on the multifunctionality of nanocomposites in delivering localized skin tumor therapy as well as inhibiting metastatic growth, which holds great promise in clinical applications.

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Section: Resultsmentioning

confidence: 99%

ZnO-based multifunctional nanocomposites to inhibit progression and metastasis of melanoma by eliciting antitumor immunity via immunogenic cell death

Zhang

Guo²,

Liu³

et al. 2020

Theranostics

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“…Focused ultrasound (FUS) is a non-invasive treatment modality that utilizes sonic energy to treat at an unlimited depth from the body surface. We and others have shown that FUS thermal therapy has an immunomodulatory effect in melanoma tumors 21 - 23 . However, tumor-heating approaches require accurate temperature feedback, and off-target effects can damage vital structures (e.g.…”

Section: Introductionmentioning

confidence: 82%

“…Cells were stained with indicated anti-mouse fluorochrome-conjugated antibody combinations for 30 min on ice in the dark using the following panel: CD45+ (tumor infiltrating leukocytes; TILs), CD11b+, F4/80+ (macrophages), CD11b+, F4/80+, MHCIIhi (M1 macrophages), CD11b+, F4/80+ MHCII lo/neg, CD206+ (M2 macrophages), CD11b+ CD11c+, F4/80-, MHCII+ (dendritic cells), CD3+, CD4+ (CD4+ T or helper Th cells), CD3+, CD4+, CD44hi CD62lo (CD4+ T effector/memory cells), and CD3+, CD8+ (CD8+ T cells). To detect IFNγ, IL-2, Granzyme-B, and Foxp3 positive T cells, cells (without stimulation) were washed after surface marker staining, fixed and permeabilized with a transcription factor buffer set (BD Biosciences), and incubated with Pe-Cy7 anti-IL-2, BV650 or APC-Cy7 anti- IFNγ, PE anti-Granzyme-B, or Alexa Fluor 488 anti-Foxp3 antibody for 30 min in the dark on ice 23 , 46 , 50 . Stained cells were run in an LSRII flow cytometer (BD Biosciences) within 24 h. Compensations were performed with single-stained UltraComp eBeads or cells.…”

Section: Methodsmentioning

confidence: 99%

Boiling histotripsy and in-situ CD40 stimulation improve the checkpoint blockade therapy of poorly immunogenic tumors

et al. 2021

Self Cite

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Background: Advanced stage cancers with a suppressive tumor microenvironment (TME) are often refractory to immune checkpoint inhibitor (ICI) therapy. Recent studies have shown that focused ultrasound (FUS) TME-modulation can synergize ICI therapy, but enhancing survival outcomes in poorly immunogenic tumors remains challenging. Here, we investigated the role of focused ultrasound based boiling histotripsy (HT) and in-situ anti-CD40 agonist antibody (αCD40) combinatorial therapy in enhancing therapeutic efficacy against ICI refractory murine melanoma. Methods: Unilateral and bilateral large (~330-400 mm 3 ) poorly immunogenic B16F10 melanoma tumors were established in the flank regions of mice. Tumors were exposed to single local HT followed by an in-situ administration of αCD40 (HT+ αCD40: HT40). Inflammatory signatures post treatment were assessed using pan-cancer immune profiling and flow cytometry. The ability of HT40 ± ICI to enhance local and systemic effects was determined by immunological characterization of the harvested tissues, and by tumor growth delay of local and distant untreated tumors 4-6 weeks post treatment. Results: Immune profiling revealed that HT40 upregulated a variety of inflammatory markers in the tumors. Immunologically, HT40 treated tumors showed an increased population of granzyme B+ expressing functional CD8+ T cells (~4-fold) as well as an increased M1 to M2 macrophage ratio (~2-3-fold) and CD8+ T: regulatory T cell ratio (~5-fold) compared to the untreated control. Systemically, the proliferation rates of the melanoma-specific memory T cell population were significantly enhanced by HT40 treatment. Finally, the combination of HT40 and ICI therapy (anti-CTLA-4 and anti-PD-L1) caused superior inhibition of distant untreated tumors, and prolonged survival rates compared to the control. Conclusions: Data suggest that HT40 reprograms immunologically cold tumors and sensitizes them to ICI therapy. This approach may be clinically useful for treating advanced stage melanoma cancers.

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“…As a consequence, the nanomicelle package conferred on PTX a more effective antitumor ability and better compatibility with the immune system, which could be combined with immunotherapy to further improve outcomes. Of note, emerging evidence has indicated promising combination benefits of nanotechnology and cancer immunotherapy 10 , 12 , 14 , 56 - 58 .…”

Section: Discussionmentioning

confidence: 99%

Nanomicelle protects the immune activation effects of Paclitaxel and sensitizes tumors to anti-PD-1 Immunotherapy

et al. 2020

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Paclitaxel (PTX) has shown pleiotropic immunologic effects on the tumor microenvironment, and nanomicelle has emerged as a promising strategy for PTX delivery. However, the detailed mechanisms remain to be fully elucidated. Meanwhile, immunogenic cell death (ICD) is an effective approach to activate the immune system. This study investigated the ICD effect of PTX and how nanomicelle affected the immune-activation ability of PTX. Methods: The ICD effects of PTX were identified via the expression of ICD markers and cell vaccine experiment. Tumor size and overall survival in multiple animal models with treatment were monitored to evaluate the antitumor effects. The mechanisms of PTX-induced ICD and antitumor immunity were determined by detecting gene expression related to ER stress and analyzing immune cell profile in tumor after treatment. Results: We revealed the immune-regulation mechanism of PTX nanomicelle by inducing ICD, which can promote antigen presentation by dendritic cells (DCs) and activate antitumor immunity. Notably, nanomicelle encapsulation protected the ICD effects and immune activation, which were hampered by immune system impairment caused by chemotherapy. Compared with traditional formulations, a low dose of nanomicelle-encapsulated PTX (nano-PTX) treatment induced immune-dependent tumor control, which increased the infiltration and function of both T cells and DCs within tumors. However, this antitumor immunity was hampered by highly expressed PD-1 on tumor-infiltrating CD8 + T cells and upregulated PD-L1 on both immune cells and tumor cells after nano-PTX treatment. Combination therapy with a low dose of nano-PTX and PD-1 antibodies elicited CD8 + T cell-dependent antitumor immunity and remarkably improved the therapeutic efficacy. Conclusions: Our results provide systemic insights into the immune-regulation ability of PTX to induce ICD, which acts as an inducer of endogenous vaccines through ICD effects, and also provides an experimental basis for clinical combination therapy with nano-PTX and PD-1 antibodies.

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Novel calreticulin-nanoparticle in combination with focused ultrasound induces immunogenic cell death in melanoma to enhance antitumor immunity

Cited by 52 publications

References 64 publications

ZnO-based multifunctional nanocomposites to inhibit progression and metastasis of melanoma by eliciting antitumor immunity via immunogenic cell death

ZnO-based multifunctional nanocomposites to inhibit progression and metastasis of melanoma by eliciting antitumor immunity via immunogenic cell death

Boiling histotripsy and in-situ CD40 stimulation improve the checkpoint blockade therapy of poorly immunogenic tumors

Nanomicelle protects the immune activation effects of Paclitaxel and sensitizes tumors to anti-PD-1 Immunotherapy

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