Visualization of the Oncolytic Alphavirus M1 Life Cycle in Cancer Cells

Lin, Na; Jia, Xudong; Xu, Cuiying; Cai, Jing; Lin, Yuan; Hu, Jun; Zhu, Wenbo; Li, Yinyin; Dong, Chen; Liu, Ying; Hu, Cheng; Gao, Yan; Liang, Jiankai; Zhang, Qinfen

doi:10.1007/s12250-020-00339-7

Cited by 4 publications

(5 citation statements)

References 32 publications

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“…RM-1 prostatic carcinoma model. TILs, tumor infiltrating T lymphocytes M1 viruses enter tumor cells via endocytosis and release their nucleocapsids in the cytoplasmic matrix for replication, during the maturation of M1 virus, envelope proteins of M1 virus are transported to the plasma membrane of tumor cells, and those proteins are considered as neoantigens which could be recognized as alien proteins by immune cells 46. Besides expressing envelop proteins on the tumor cell surface, M1 also kill tumor cells directly and release more neoantigens to induce immune responses 40.…”

mentioning

confidence: 99%

Cytotoxic T lymphocyte‐associated protein 4 antibody aggrandizes antitumor immune response of oncolytic virus M1 via targeting regulatory T cells

Liu

et al. 2021

Intl Journal of Cancer

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Oncolytic virotherapies are perceived as remarkable immunotherapies coming into view and represent highly promising cancer treatments, yet to figure out its specific immune responses and underlying barriers remains critical. Albeit recent studies have demonstrated that oncolytic viruses (OVs) could fine tune tumor microenvironment (TME) to elicit tumor suppression mainly due to effective Tcell responses, the interaction between suppressive T cells and OVs is barely undetermined. Herein, we found that regulatory T cells (Treg cells) were increased in the TME following systemic administration of oncolytic virus M1 along with the higher expression of relative cytokines and chemokines in both mouse RM-1 prostatic carcinoma model and mouse B16F10 melanoma model. Besides, Treg cells expressed high levels of CD25 post-M1 treatment, and its suppressive effect on CD8 + T cells was also elevated. Depletion of Treg cells in M1-treated groups significantly reinforced antitumor effect of M1. Specific targeting of Treg cells using cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody (Ab) in combination with M1 treatment elicited a more profound tumor suppression and longer overall survival time than M1 alone in both tumor models. Moreover, CTLA-4 Ab further aggrandized antitumor immune response elicited by M1, including increased infiltration of CD45 + immune cells and CD8 + or CD4 + T lymphocytes, decreased ratio of Treg cells to CD4 + T lymphocytes, the intensified lymphocytotoxicity and elevated secretion of cytotoxic cytokines like interferon-γ, granzyme B and perforin. Therefore, our findings constituted a suggestive evidence that targeting Treg cells in M1-based oncolytic virotherapy may achieve a highly response in clinical cancer research.

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confidence: 99%

Cytotoxic T lymphocyte‐associated protein 4 antibody aggrandizes antitumor immune response of oncolytic virus M1 via targeting regulatory T cells

Liu

et al. 2021

Intl Journal of Cancer

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“…In addition to RGNNV and SV40, the time of appearance, rather than the number, of SFV-induced vacuolization was also affected by the multiplicity of SFV infections [ 31 ]. Similarly, the number and size of vacuoles induced by Oncolytic alphavirus M1 in HepG2 cells gradually increased with virus infection time at 6 h, 12 h and 18 hpi [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

“…Many ZIKV RNAs and E proteins are concentrated at the vacuole borders, suggesting that vacuole formation may promote virus release and spread [ 32 ]. Additionally, three types of cytopathic vacuoles are formed during the early and late stage of Oncolytic alphavirus M1 infection, suggesting their involvement in the replication, maturation and release of the virus [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several viruses such as Alphavirus, simian virus (SV40), and Semliki Forest Virus (SFV) have been shown to cause dramatic cytoplasmic vacuolization [ 1–3 ]. SV40 is the only known polyomavirus with obvious vacuolizing activities and usually induces vacuoles at late infection stages, suggesting that vacuolization may be coincident with progeny virus release.…”

Section: Introductionmentioning

confidence: 99%

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Nervous necrosis virus induced vacuolization is a Rab5- and actin-dependent process

Liu,

Wang,

Zhang

et al. 2024

Virulence

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Cytoplasmic vacuolization is commonly induced by bacteria and viruses, reflecting the complex interactions between pathogens and the host. However, their characteristics and formation remain unclear. Nervous necrosis virus (NNV) infects more than 100 global fish species, causing enormous economic losses. Vacuolization is a hallmark of NNV infection in host cells, but remains a mystery. In this study, we developed a simple aptamer labelling technique to identify red-spotted grouper NNV (RGNNV) particles in fixed and live cells to explore RGNNV-induced vacuolization. We observed that RGNNV-induced vacuolization was positively associated with the infection time and virus uptake. During infection, most RGNNV particles, as well as viral genes, colocalized with vacuoles, but not giant vacuoles > 3 μm in diameter. Although the capsid protein (CP) is the only structural protein of RGNNV, its overexpression did not induce vacuolization, suggesting that vacuole formation probably requires virus entry and replication. Given that small Rab proteins and the cytoskeleton are key factors in regulating cellular vesicles, we further investigated their roles in RGNNV-induced vacuolization. Using live cell imaging, Rab5, a marker of early endosomes, was continuously located in vacuoles bearing RGNNV during giant vacuole formation. Rab5 is required for vacuole formation and interacts with CP according to siRNA interference and Co-IP analysis. Furthermore, actin formed distinct rings around small vacuoles, while vacuoles were located near microtubules. Actin, but not microtubules, plays an important role in vacuole formation using chemical inhibitors. These results provide valuable insights into the pathogenesis and control of RGNNV infections.

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“…The naturally oncolytic M1 alphavirus can selectively infect and kill zinc finger antiviral protein (ZAP)-deficient tumor cells without causing damage to normal cells [ 61 ]. The key stages of infection and replication of M1 have been visualized using transmission electron microscopy (TEM) in the HepG2 liver cancer cell line [ 62 ]. M1 induced typical apoptotic events such as vacuolization of cancer cells and nuclear marginalization.…”

Section: Alphavirus-based Immunotherapy For Cancermentioning

confidence: 99%

Alphaviruses in Immunotherapy and Anticancer Therapy

Lundström¹

2022

Biomedicines

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Alphaviruses have been engineered as expression vectors for vaccine development and gene therapy. Due to the feature of RNA self-replication, alphaviruses can provide exceptional direct cytoplasmic expression of transgenes based on the delivery of recombinant particles, naked or nanoparticle-encapsulated RNA or plasmid-based DNA replicons. Alphavirus vectors have been utilized for the expression of various antigens targeting different types of cancers, and cytotoxic and antitumor genes. The most common alphavirus vectors are based on the Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus, but the oncolytic M1 alphavirus has also been used. Delivery of immunostimulatory cytokine genes has been the basis for immunotherapy demonstrating efficacy in different animal tumor models for brain, breast, cervical, colon, lung, ovarian, pancreatic, prostate and skin cancers. Typically, therapeutic effects including tumor regression, tumor eradication and complete cure as well as protection against tumor challenges have been observed. Alphavirus vectors have also been subjected to clinical evaluations. For example, therapeutic responses in all cervical cancer patients treated with an alphavirus vector expressing the human papilloma virus E6 and E7 envelope proteins have been achieved.

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Visualization of the Oncolytic Alphavirus M1 Life Cycle in Cancer Cells

Cited by 4 publications

References 32 publications

Cytotoxic T lymphocyte‐associated protein 4 antibody aggrandizes antitumor immune response of oncolytic virus M1 via targeting regulatory T cells

Cytotoxic T lymphocyte‐associated protein 4 antibody aggrandizes antitumor immune response of oncolytic virus M1 via targeting regulatory T cells

Nervous necrosis virus induced vacuolization is a Rab5- and actin-dependent process

Alphaviruses in Immunotherapy and Anticancer Therapy

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