Development of a VLP-Based Vaccine Displaying an xCT Extracellular Domain for the Treatment of Metastatic Breast Cancer

Rolih, Valeria; Caldeira, Jerri C.; Bolli, Elisabetta; Salameh, Ahmad; Conti, Laura; Barutello, Giuseppina; Riccardo, Federica; Magri, Jolanda; Lamolinara, Alessia; Parra, Karla; Valenzuela, Paloma; Francia, Giulio; Iezzi, Manuela; Pericle, Federica; Cavallo, Federica

doi:10.3390/cancers12061492

Cited by 26 publications

(23 citation statements)

References 56 publications

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“…A bacteriophage MS2 VLP-based vaccine that displayed the extracellular loop of xCT transporter on its surface was used to treat mice carrying metastatic breast cancer cells. The treated animals produced high levels of specific antibodies and reduced metastasis [200]. Bolli et al developed the AX09-0M6 as a VLP-based vaccine platform by displaying of the human xCT extracellular domain (ECD6) on its surface.…”

Section: Vlp-based Vaccines Developed Against Breast Cancermentioning

confidence: 99%

Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers

et al. 2021

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Virus-like particles (VLPs) are virus-derived structures made up of one or more different molecules with the ability to self-assemble, mimicking the form and size of a virus particle but lacking the genetic material so they are not capable of infecting the host cell. Expression and self-assembly of the viral structural proteins can take place in various living or cell-free expression systems after which the viral structures can be assembled and reconstructed. VLPs are gaining in popularity in the field of preventive medicine and to date, a wide range of VLP-based candidate vaccines have been developed for immunization against various infectious agents, the latest of which is the vaccine against SARS-CoV-2, the efficacy of which is being evaluated. VLPs are highly immunogenic and are able to elicit both the antibody- and cell-mediated immune responses by pathways different from those elicited by conventional inactivated viral vaccines. However, there are still many challenges to this surface display system that need to be addressed in the future. VLPs that are classified as subunit vaccines are subdivided into enveloped and non- enveloped subtypes both of which are discussed in this review article. VLPs have also recently received attention for their successful applications in targeted drug delivery and for use in gene therapy. The development of more effective and targeted forms of VLP by modification of the surface of the particles in such a way that they can be introduced into specific cells or tissues or increase their half-life in the host is likely to expand their use in the future. Recent advances in the production and fabrication of VLPs including the exploration of different types of expression systems for their development, as well as their applications as vaccines in the prevention of infectious diseases and cancers resulting from their interaction with, and mechanism of activation of, the humoral and cellular immune systems are discussed in this review.

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Section: Vlp-based Vaccines Developed Against Breast Cancermentioning

confidence: 99%

Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers

et al. 2021

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“…These NK cells in the immune infiltrate can mediate an antibody-dependent cellular cytotoxicity (ADCC) via the recognition of anti-xCT IgG2a antibodies induced by vaccination [ 55 ]. In a similar way, a newer VLP vaccine that displays the third extracellular domain of xCT (ECD3), whose sequence is longer than that of ECD6, resulting in a major oligoclonal antibody response, can neutralize xCT function and impair breast cancer cell proliferation and metastasization [ 61 ]. Finally, the bovine herpesvirus 4 (BoHV-4)-based anti-xCT vaccine, which exploits a safe viral vector that confers immunogenicity to tumor antigens, has proven to be effective in impairing lung metastasis and inducing T lymphocyte activation, anti-xCT antibody production and ADCC in mouse mammary cancer models [ 53 ].…”

Section: The Cystine/glutamate Antiporter Xctmentioning

confidence: 99%

Tumor-Associated Antigen xCT and Mutant-p53 as Molecular Targets for New Combinatorial Antitumor Strategies

Magri

Gasparetto

Conti

et al. 2021

Cells

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The cystine/glutamate antiporter xCT is a tumor-associated antigen that has been newly identified in many cancer types. By participating in glutathione biosynthesis, xCT protects cancer cells from oxidative stress conditions and ferroptosis, and contributes to metabolic reprogramming, thus promoting tumor progression and chemoresistance. Moreover, xCT is overexpressed in cancer stem cells. These features render xCT a promising target for cancer therapy, as has been widely reported in the literature and in our work on its immunotargeting. Interestingly, studies on the TP53 gene have revealed that both wild-type and mutant p53 induce the post-transcriptional down modulation of xCT, contributing to ferroptosis. Moreover, APR-246, a small molecule drug that can restore wild-type p53 function in cancer cells, has been described as an indirect modulator of xCT expression in tumors with mutant p53 accumulation, and is thus a promising drug to use in combination with xCT inhibition. This review summarizes the current knowledge of xCT and its regulation by p53, with a focus on the crosstalk of these two molecules in ferroptosis, and also considers some possible combinatorial strategies that can make use of APR-246 treatment in combination with anti-xCT immunotargeting.

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“…Therefore, xCT contributes to the maintenance of a reducing TME that may preserve HMGB1 ability to activate TLR2 [ 103 ]. We have previously demonstrated that xCT protects breast CSCs from oxidative stress and chemotherapy, and we have developed different anti-xCT vaccines that decrease tumor growth and metastasis in breast cancer mouse models [ 76 , 101 , 102 , 104 , 105 ]. We hypothesize that the ability of xCT immunotargeting to inhibit the HMGB1/TLR2 axis may contribute to its therapeutic activity and suggest that it would be worth developing combined therapies targeting these two mechanisms responsible for tumor survival and progression.…”

Section: Effect Of Chemo and Radiotherapy On Tlr2 Activationmentioning

confidence: 99%

Toll-Like Receptor 2 at the Crossroad between Cancer Cells, the Immune System, and the Microbiota

Lorenzo

Bolli

Tarone

et al. 2020

IJMS

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Toll-like receptor 2 (TLR2) expressed on myeloid cells mediates the recognition of harmful molecules belonging to invading pathogens or host damaged tissues, leading to inflammation. For this ability to activate immune responses, TLR2 has been considered a player in anti-cancer immunity. Therefore, TLR2 agonists have been used as adjuvants for anti-cancer immunotherapies. However, TLR2 is also expressed on neoplastic cells from different malignancies and promotes their proliferation through activation of the myeloid differentiation primary response protein 88 (MyD88)/nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway. Furthermore, its activation on regulatory immune cells may contribute to the generation of an immunosuppressive microenvironment and of the pre-metastatic niche, promoting cancer progression. Thus, TLR2 represents a double-edge sword, whose role in cancer needs to be carefully understood for the setup of effective therapies. In this review, we discuss the divergent effects induced by TLR2 activation in different immune cell populations, cancer cells, and cancer stem cells. Moreover, we analyze the stimuli that lead to its activation in the tumor microenvironment, addressing the role of danger, pathogen, and microbiota-associated molecular patterns and their modulation during cancer treatments. This information will contribute to the scientific debate on the use of TLR2 agonists or antagonists in cancer treatment and pave the way for new therapeutic avenues.

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Development of a VLP-Based Vaccine Displaying an xCT Extracellular Domain for the Treatment of Metastatic Breast Cancer

Cited by 26 publications

References 56 publications

Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers

Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers

Tumor-Associated Antigen xCT and Mutant-p53 as Molecular Targets for New Combinatorial Antitumor Strategies

Toll-Like Receptor 2 at the Crossroad between Cancer Cells, the Immune System, and the Microbiota

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