Synergistic STING activation by PC7A nanovaccine and ionizing radiation improves cancer immunotherapy

Luo, Min; Liu, Zhida; Zhang, Xinyi; Han, Chuanhui; Samandi, Layla; Dong, Chunbo; Sumer, Baran D.; Lea, Jayanthi; Fu, Yang Xin; Gao, Jinming

doi:10.1016/j.jconrel.2019.02.036

Cited by 70 publications

(61 citation statements)

References 33 publications

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“…Since antigen escape into the cytosol is a rate‐limiting step during the process, the introduction of PC7A, which is capable of enhancing endosomal escape in an acidic environment, enables more efficient MHC I presentation to CD8 + T cells . As reported previously, PC7A can activate the “stimulator of interferon genes” (STING) pathway, thereby increasing DC maturation and proliferation for both NK cells and T cells …”

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confidence: 83%

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles

et al. 2019

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Neoantigens induced by random mutations and specific to an individual's cancer are the most important tumor antigens recognized by T cells. Among immunologically “cold” tumors, limited recognition of tumor neoantigens results in the absence of a de novo antitumor immune response. These “cold” tumors present a clinical challenge as they are poorly responsive to most immunotherapies, including immune checkpoint inhibitors (ICIs). Radiation therapy (RT) can enhance immune recognition of “cold” tumors, resulting in a more diversified antitumor T‐cell response, yet RT alone rarely results in a systemic antitumor immune response. Therefore, a multifunctional bacterial membrane‐coated nanoparticle (BNP) composed of an immune activating PC7A/CpG polyplex core coated with bacterial membrane and imide groups to enhance antigen retrieval is developed. This BNP can capture cancer neoantigens following RT, enhance their uptake in dendritic cells (DCs), and facilitate their cross presentation to stimulate an antitumor T‐cell response. In mice bearing syngeneic melanoma or neuroblastoma, treatment with BNP+RT results in activation of DCs and effector T cells, marked tumor regression, and tumor‐specific antitumor immune memory. This BNP facilitates in situ immune recognition of a radiated tumor, enabling a novel personalized approach to cancer immunotherapy using off‐the‐shelf therapeutics.

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confidence: 83%

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles

et al. 2019

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“…Similarly, inhalable phosphatidylserine liposomes loaded with cGAMP synergized with IR, better controlling metastases than either monotherapies, even outside of the irradiated area in B16-OVA and 4T1 lung metastases models [ 90 ]. A STING-activating nanovaccine (i.e., PC7A nanoparticle loaded with antigen) synergized with IR in TC-1 tumor models better controlling local irradiated tumors and distal unirradiated tumors than either treatment alone [ 120 ]. Lastly, RR-CDG (a STING agonist) synergized with IR in Panc02 pancreatic cancer models, producing robust CD8+ T cell responses that exerted control of both local and distant tumors [ 121 ].…”

Section: Augmenting Sting Signaling To Enhance Radiation-induced Amentioning

confidence: 99%

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Storozynsky

Hitt

2020

IJMS

122

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Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

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“…These fibrils have been assembled with various epitopes of Plasmodium falciparum [66] , Mycobacterium tuberculosis [67] , Streptococcus aureus [68] , T-helper cells epitope PADRE [68] and OVA epitopes [69] . Conjugation of E2EP3 immunogenic epitope of Chikungunya virus E2 glycoprotein with β-sheet self-adjuvanted amyloid assemblies showed cytocompatibility with enhanced macrophage uptake and robust IgG response against E2EP3 epitope [70] . Self-assembling protein nanoparticles (SAPNs) are 20-30 nm icosahedrons containing pentameric and trimeric helical coiledcoils conjugated with (glycine) 2 linker (refer Fig.…”

Section: Protein/peptide-based Nanovaccinesmentioning

confidence: 99%

Advancements in prophylactic and therapeutic nanovaccines

et al. 2020

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Synergistic STING activation by PC7A nanovaccine and ionizing radiation improves cancer immunotherapy

Cited by 70 publications

References 33 publications

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Advancements in prophylactic and therapeutic nanovaccines

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