CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer

Li, Yang; Zhang, Hui; Li, Qin; Zou, Pingjin; Huang, Xingxiang; Wu, Chih Yang; Li, Tan

doi:10.1016/j.canlet.2020.09.011

Cited by 67 publications

(42 citation statements)

References 53 publications

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“…Delivery of ICD inducers, such as SR-4835 (a CDK12/13-specific inhibitor), RIG-I agonists and chemotherapeutics, as well as photothermal agents, with synthetic nanoparticles, has been confirmed to have therapeutic potential in several preclinical models of breast cancer [45][46][47]. Although Texs play a major role in tumor immune evasion and growth, they can be manipulated and have tumor-homing properties, as well as low in vivo toxicity and immunogenicity [48].…”

Section: Discussionmentioning

confidence: 99%

Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer

et al. 2022

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Background Dendritic cells (DCs) are central for the initiation and regulation of innate and adaptive immunity in the tumor microenvironment. As such, many kinds of DC-targeted vaccines have been developed to improve cancer immunotherapy in numerous clinical trials. Targeted delivery of antigens and adjuvants to DCs in vivo represents an important approach for the development of DC vaccines. However, nonspecific activation of systemic DCs and the preparation of optimal immunodominant tumor antigens still represent major challenges. Methods We loaded the immunogenic cell death (ICD) inducers human neutrophil elastase (ELANE) and Hiltonol (TLR3 agonist) into α-lactalbumin (α-LA)-engineered breast cancer-derived exosomes to form an in situ DC vaccine (HELA-Exos). HELA-Exos were identified by transmission electron microscopy, nanoscale flow cytometry, and Western blot analysis. The targeting, killing, and immune activation effects of HELA-Exos were evaluated in vitro. The tumor suppressor and immune-activating effects of HELA-Exos were explored in immunocompetent mice and patient-derived organoids. Results HELA-Exos possessed a profound ability to specifically induce ICD in breast cancer cells. Adequate exposure to tumor antigens and Hiltonol following HELA-Exo-induced ICD of cancer cells activated type one conventional DCs (cDC1s) in situ and cross-primed tumor-reactive CD8+ T cell responses, leading to potent tumor inhibition in a poorly immunogenic triple negative breast cancer (TNBC) mouse xenograft model and patient-derived tumor organoids. Conclusions HELA-Exos exhibit potent antitumor activity in both a mouse model and human breast cancer organoids by promoting the activation of cDC1s in situ and thus improving the subsequent tumor-reactive CD8+ T cell responses. The strategy proposed here is promising for generating an in situ DC-primed vaccine and can be extended to various types of cancers. Graphic Abstract Scheme 1. Schematic illustration of HELA-Exos as an in situ DC-primed vaccine for breast cancer. (A) Allogenic breast cancer-derived exosomes isolated from MDA-MB-231 cells were genetically engineered to overexpress α-LA and simultaneously loaded with the ICD inducers ELANE and Hiltonol (TLR3 agonist) to generate HELA-Exos. (B) Mechanism by which HELA-Exos activate DCs in situ in a mouse xenograft model ofTNBC. HELA-Exos specifically homed to the TME and induced ICD in cancer cells, which resulted in the increased release of tumor antigens, Hiltonol, and DAMPs, as well as the uptake of dying tumor cells by cDC1s. The activated cDC1s then cross-primed tumor-reactive CD8+ T cell responses. (C) HELA-Exos activated DCs in situ in the breast cancer patient PBMC-autologous tumor organoid coculture system. Abbreviations: DCs: dendritic cells; α-LA: α-lactalbumin; HELA-Exos: Hiltonol-ELANE-α-LA-engineered exosomes; ICD: immunogenic cell death; ELANE: human neutrophil elastase; TLR3: Toll-like receptor 3; TNBC: triple-negative breast cancer; TME: tumor microenvironment; DAMPs: damage-associated molecular patterns; cDC1s: type 1 conventional dendritic cells; PBMCs: peripheral blood mononuclear cells

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Section: Discussionmentioning

confidence: 99%

Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer

et al. 2022

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“…The notion of immunogenic cell death was described as the unique type of regulated cell death, able to trigger full antigenspecific adaptive immunological responses by emitting danger signals or DAMPs (1,3,14). The combination of immunogenic therapeutic and novel immunotherapeutic regimens holds great promise for treating malignancies (15)(16)(17)(18). Therefore, it could be advantageous to identify ICD-related biomarkers that help distinguish HNSCC patients premised on the benefits they derive from immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

An Immunogenic Cell Death-Related Classification Predicts Prognosis and Response to Immunotherapy in Head and Neck Squamous Cell Carcinoma

Wang

Wu²,

Liu³

et al. 2021

Front. Immunol.

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Immunogenic cell death (ICD) has been classified as a form of regulated cell death (RCD) that is sufficient to activate an adaptive immune response. Accumulating evidence has demonstrated the ability of ICD to reshape the tumor immune microenvironment through the emission of danger signals or DAMPs, which may contribute to the immunotherapy. Currently, identification of ICD-associated biomarkers that stratify patients according to their benefit from ICD immunotherapy would be of great advantage. Here, we identified two ICD-associated subtypes by consensus clustering. ICD-high subtype was associated with the favorable clinical outcomes, abundant immune cell infiltration, and high activity of immune response signaling. Besides, we established and validated an ICD-related prognostic model that predicted the survival of HNSCC and was associated with tumor immune microenvironment. In conclusion, we established a new classification system of HNSCC based on ICD signatures. This stratification had significant clinical outcomes for estimating prognosis, as well as the immunotherapy of HNSCC patients

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“…Several recent clinical reports now corroborate this hypothesis as the sequential combination of ICD induction by chemo- or radiotherapy with PD-1 checkpoint blockade achieved excellent therapeutic efficacy in several neoplastic indications including breast and small cell lung cancer. 17–23 …”

Section: Introductionmentioning

confidence: 99%

Carbon ion radiotherapy triggers immunogenic cell death and sensitizes melanoma to anti-PD-1 therapy in mice

Zhou

Yang

et al. 2022

OncoImmunology

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Carbon ion radiotherapy (CIRT) is an emerging type of radiotherapy for the treatment of solid tumors. In recent years, evidence accumulated that CIRT improves the therapeutic outcome in patients with otherwise poor response to immune checkpoint blockade. Here, we aimed at identifying the underlying mechanisms of CIRT-induced tumor immunogenicity and treatment efficacy. We used human U2OS osteosarcoma cells for the in vitro assessment of immunogenic cell death and established several in vivo models of melanoma in mice. We treated the animals with conventional radiation, CIRT, PD-1-targeting immune checkpoint blockade or a sequential combinations of radiotherapy with checkpoint blockade. We utilized flow cytometry, polyacrylamide gel electrophoresis (PAGE) and immunoblot analysis, immunofluorescence, immunohistochemistry, as well as enzyme-linked immunosorbent assays (ELISA) to assess biomarkers of immunogenic cell death in vitro. Treatment efficacy was studied by tumor growth assessment and the tumor immune infiltrate was analyzed by flow cytometry and immunohistochemistry. Compared with conventional radioimmunotherapy, the combination of CIRT with anti-PD-1 more efficiently triggered traits of immunogenic cell death including the exposure of calreticulin, the release of adenosine triphosphate (ATP), the exodus of high-mobility group box 1 (HMGB1) as well as the induction of type-1 interferon responses. In addition, CIRT plus anti-PD-1 led to an increased infiltration of CD4 + , and CD8 + lymphocytes into the tumor bed, significantly decreased tumor growth and prolonged survival of melanoma bearing mice. We herein provide evidence that CIRT-triggered immunogenic cell death, enhanced tumor immunogenicity and improved the efficacy of subsequent anti-PD-1 immunotherapy.

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CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer

Cited by 67 publications

References 53 publications

Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer

Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer

An Immunogenic Cell Death-Related Classification Predicts Prognosis and Response to Immunotherapy in Head and Neck Squamous Cell Carcinoma

Carbon ion radiotherapy triggers immunogenic cell death and sensitizes melanoma to anti-PD-1 therapy in mice

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