Imiquimod-gemcitabine nanoparticles harness immune cells to suppress breast cancer

Singh, Bijay; Maharjan, Sushila; Pan, Dongli; Zhao, Zongmin; Gao, Yongsheng; Zhang, Yu Shrike; Mitragotri, Samir

doi:10.1016/j.biomaterials.2021.121302

Cited by 31 publications

(18 citation statements)

References 46 publications

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“…However, the strategies attempting to reactivate CD8 + T cells tend to have possible drug toxicities and high costs, and targeting CD8 + T cells alone does not provide enough efficacy for successful cancer treatment considering the complexity of the immunosuppressive microenvironment ( 9 , 60 ). Moreover, the efficacy of immunotherapy varies dramatically across cancer types, and only a minor subset of TNBC patients is associated with immunotherapy benefits ( 8 , 10 , 22 ). Thus, it becomes more important to develop newer approaches for breast cancer treatment using the existing chemotherapy drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Although immunotherapy exhibited promising therapeutic effects for TNBC in combination with chemotherapy or molecularly targeted therapy, only a small portion of patients respond well to the novel therapy (6)(7)(8)(9). Thus, considering the complexity of immunotherapy and their normally high treatment costs, it becomes more meaningful to develop newer combination therapies with broad-spectrum anticancer activity, high efficiency and low toxicity for TNBC based on existing chemotherapy drugs (10).…”

Section: Introductionmentioning

confidence: 99%

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Single-cell RNA-sequencing uncovers compound kushen injection synergistically improves the efficacy of chemotherapy by modulating the tumor environment of breast cancer

Liu

Bai²,

Li³

et al. 2022

Front. Immunol.

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BackgroundDue to lack of enough specific targets and the immunosuppressive tumor microenvironment (TME) of triple-negative breast cancer (TNBC), TNBC patients often cannot benefit from a single treatment option. This study aims to explore the regulatory effects of Compound kushen injection (CKI) plus chemotherapy on the TME of TNBC from a single cell level.MethodsA mouse TNBC model in BALB/c mice was established to evaluate the antitumor efficacy and toxicity of CKI combined with chemotherapy. Flow cytometry was used to observe the influence of CKI on the lymphocyte populations in the tumor bearing mice. Both bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) were applied to portray the modulation of CKI combined with chemotherapy on the TME of TNBC mice.ResultsCKI significantly enhanced the anticancer activity of chemotherapy in vivo with no obvious side effects. Flow cytometry results revealed a significantly higher activation of CD8+ T lymphocytes in the spleens and tumors of the mice with combination therapy. Bulk RNA-seq indicated that CKI could promote the cytotoxic immune cell infiltrating into tumor tissues. Meanwhile, scRNA-seq further revealed that CKI combined with chemotherapy could enhance the percentage of tumor-infiltrating CD8+ T cells, inhibit tumor-promoting signaling pathways, and promote T cell activation and positive regulation of immune response. In addition, CKI showed obvious anticancer activity against MDA-MB-231 breast tumor cells in vitro.ConclusionsThe combination of CKI and chemotherapy might provide a higher efficiency and lower toxicity strategy than a single chemotherapy drug for TNBC. CKI potentiates the anti-TNBC effects of chemotherapy by activating anti-tumor immune response in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Single-cell RNA-sequencing uncovers compound kushen injection synergistically improves the efficacy of chemotherapy by modulating the tumor environment of breast cancer

Liu

Bai²,

Li³

et al. 2022

Front. Immunol.

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“…With the expanding number of novel NDDS able to elicit combination therapeutic effects, there is increasing interest in the use of TOCs to interrogate the tumor immune microenvironment. For instance, Bijay et al used a microfluidics-based 3D, compartmentalized breast cancer-on-a-chip (BCC) to study immune cell recruitment by the developed NDDS [ 101 ]. In their BCC, breast cancer cells were loaded in the bottom chamber and THP-1 cells (substitutes of macrophages in the in vitro culture) were circulated through the fluidic channel.…”

Section: Tumor-on-a-chip Platforms For Preclinical Evaluations Of Nan...mentioning

confidence: 99%

Tumor-on-a-chip model for advancement of anti-cancer nano drug delivery system

et al. 2022

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Despite explosive growth in the development of nano-drug delivery systems (NDDS) targeting tumors in the last few decades, clinical translation rates are low owing to the lack of efficient models for evaluating and predicting responses. Microfluidics-based tumor-on-a-chip (TOC) systems provide a promising approach to address these challenges. The integrated engineered platforms can recapitulate complex in vivo tumor features at a microscale level, such as the tumor microenvironment, three-dimensional tissue structure, and dynamic culture conditions, thus improving the correlation between results derived from preclinical and clinical trials in evaluating anticancer nanomedicines. The specific focus of this review is to describe recent advances in TOCs for the evaluation of nanomedicine, categorized into six sections based on the drug delivery process: circulation behavior after infusion, endothelial and matrix barriers, tumor uptake, therapeutic efficacy, safety, and resistance. We also discuss current issues and future directions for an end-use perspective of TOCs.

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“…To limit the systemic exposure, which causes severe side effects and toxicity, TLR7/8 agonists are predominantly employed locally [13,14]. Topical application of imiquimod (TLR7 agonist) or resiquimod (TLR7/8 agonist) has been used successfully to treat several murine tumor models [15][16][17], while resiquimod has also demonstrated efficacy in early-stage cutaneous T-cell lymphoma [18]. Imiquimod is also approved as a topical treatment for actinic keratosis and superficial basal cell carcinoma [19,20].…”

Section: Introductionmentioning

confidence: 99%

Local immunotherapy with the RNA-based immune stimulator CV8102 induces substantial anti-tumor responses and enhances checkpoint inhibitor activity

Lutz

Meister²,

Habbeddine³

et al. 2022

Cancer Immunol Immunother

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Immunotherapy has revolutionized cancer treatment in recent years. Although currently approved checkpoint inhibitors (CPIs) yield remarkable anti-tumoral responses in several cancer types, a substantial proportion of patients do not benefit from such therapies. Local activation of innate immune signaling pathways is a promising approach to overcome the immunosuppressive tumor microenvironment, induce anti-tumor immunity, and improve the efficacy of CPI therapies. Here, we assessed the mode of action and efficacy of the RNA-based innate immune stimulator CV8102 for local immunotherapy in preclinical models. Intratumoral (i.t.) administration of CV8102 activated innate immune responses in the tumor microenvironment and draining lymph nodes, resulting in a dose-dependent anti-tumoral response. Combining i.t. CV8102 with systemic anti-programmed death protein 1 (PD-1) treatment further enhanced anti-tumoral responses, inducing tumor infiltration and activation of CD8+ T cells. The resulting memory response prevented tumor growth in rechallenged animals and impaired the growth of non-injected distal tumors. Therefore, i.t. CV8102 delivery is a promising approach for local cancer immunotherapy, especially in combination with CPIs. Clinical testing of CV8102 is ongoing (NCT03291002).

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Imiquimod-gemcitabine nanoparticles harness immune cells to suppress breast cancer

Cited by 31 publications

References 46 publications

Single-cell RNA-sequencing uncovers compound kushen injection synergistically improves the efficacy of chemotherapy by modulating the tumor environment of breast cancer

Single-cell RNA-sequencing uncovers compound kushen injection synergistically improves the efficacy of chemotherapy by modulating the tumor environment of breast cancer

Tumor-on-a-chip model for advancement of anti-cancer nano drug delivery system

Local immunotherapy with the RNA-based immune stimulator CV8102 induces substantial anti-tumor responses and enhances checkpoint inhibitor activity

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