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Oncolytic herpes virus G47Δ injected into tongue cancer swiftly traffics in lymphatics and suppresses metastasis.

ABSTRACT: The prognosis of oral squamous cell carcinoma (OSCC) largely depends on the control of lymph node metastases. We evaluate the therapeutic efficacy of G47Δ, a third-generation oncolytic herpes simplex virus type 1 (HSV-1), in mouse tongue cancer models. Intratumoral injection with G47Δ prolonged the survival in all orthotopic models investigated. In both athymic and immunocompetent models, G47Δ injected into the tongue cancer swiftly traffics to the draining cervical lymph nodes and suppresses lymph node metastases. In the immunocompetent KLN205-MUC1 model, in which the metastatic cascade that tongue cancer patients commonly experience is reproduced, intratumoral G47Δ injection even immediately prior to a tumor resection prolonged survival. Cervical lymph nodes 18 h after G47Δ treatment showed the presence of G47Δ infection and an increase in CD69-positive cells, indicating an immediate activation of T cells. Furthermore, G47Δ injected directly into enlarged metastatic lymph nodes significantly prolonged the survival at an advanced stage. Whereas intratumorally injected oncolytic HSV-1 does not readily circulate in the blood stream, G47Δ is shown to traffic in the lymphatics swiftly. The use of G47Δ can lead to entirely new treatment strategies for tongue cancer and other OSCC at all clinical stages.

SUBMITTER: Uchihashi T

PROVIDER: S-EPMC8430046 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Oncolytic herpes virus G47Δ injected into tongue cancer swiftly traffics in lymphatics and suppresses metastasis.

Uchihashi Toshihiro T Nakahara Hirokazu H Fukuhara Hiroshi H Iwai Miwako M Ito Hirotaka H Sugauchi Akinari A Tanaka Minoru M Kogo Mikihiko M Todo Tomoki T

Molecular therapy oncolytics 20210624

The prognosis of oral squamous cell carcinoma (OSCC) largely depends on the control of lymph node metastases. We evaluate the therapeutic efficacy of G47Δ, a third-generation oncolytic herpes simplex virus type 1 (HSV-1), in mouse tongue cancer models. Intratumoral injection with G47Δ prolonged the survival in all orthotopic models investigated. In both athymic and immunocompetent models, G47Δ injected into the tongue cancer swiftly traffics to the draining cervical lymph nodes and suppresses ly ...[more]

PMID: 34553027

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Project description:BackgroundDysregulation of cholesterol metabolism is associated with the metastasis of triple-negative breast cancer (TNBC). Apolipoprotein A1 (ApoA1) is widely recognized for its pivotal role in regulating cholesterol efflux and maintaining cellular cholesterol homeostasis. However, further exploration is needed to determine whether it inhibits TNBC metastasis by affecting cholesterol metabolism. Additionally, it is necessary to investigate whether ApoA1-based oncolytic virus therapy can be used to treat TNBC.MethodsIn vitro experiments and mouse breast cancer models were utilized to evaluate the molecular mechanism of ApoA1 in regulating cholesterol efflux and inhibiting breast cancer progression and metastasis. The gene encoding ApoA1 was inserted into the adenovirus genome to construct a recombinant adenovirus (ADV-ApoA1). Subsequently, the efficacy of ADV-ApoA1 in inhibiting the growth and metastasis of TNBC was evaluated in several mouse models, including orthotopic breast cancer, spontaneous breast cancer, and human xenografts. In addition, a comprehensive safety assessment of Syrian hamsters and rhesus monkeys injected with oncolytic adenovirus was conducted.ResultsThis study found that dysregulation of cholesterol homeostasis is critical for the progression and metastasis of TNBC. In a mouse orthotopic model of TNBC, a high-cholesterol diet promoted lung and liver metastasis, which was associated with keratin 14 (KRT14), a protein responsible for TNBC metastasis. Furthermore, studies have shown that ApoA1, a cholesterol reverse transporter, inhibits TNBC metastasis by regulating the cholesterol/IKBKB/FOXO3a/KRT14 axis. Moreover, ADV-ApoA1 was found to promote cholesterol efflux, inhibit tumor growth, reduce lung metastasis, and prolonged the survival of mice with TNBC. Importantly, high doses of ADV-ApoA1 administered intravenously and subcutaneously were well tolerated in rhesus monkeys and Syrian hamsters.ConclusionsThis study provides a promising oncolytic virus treatment strategy for TNBC based on targeting dysregulated cholesterol metabolism. It also establishes a basis for subsequent clinical trials of ADV-ApoA1 in the treatment of TNBC.

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Oncolytic herpes virus G47Δ injected into tongue cancer swiftly traffics in lymphatics and suppresses metastasis.

Publications

Oncolytic herpes virus G47Δ injected into tongue cancer swiftly traffics in lymphatics and suppresses metastasis.

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