Alphavirus-driven Interferon Gamma (IFNg) Expression Inhibits Tumour Growth in Orthotopic 4T1 Breast Cancer Model

Trofimova, Olga; Korotkaja, Ksenija; Skrastiņa, Dace; Jansons, Juris; Spunde, Karīna; Isaguliants, Maria; Zajakina, Anna

doi:10.20944/preprints202108.0536.v1

Cited by 9 publications

(1 citation statement)

References 98 publications

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“…A replication-deficient Semliki Forest virus (SFV) vector, expressing IFNg (SFV/IFNg) was utilized as a safer viral mediated delivery option and ideal for macrophage polarization, as SFVs do not infect human or murine macrophages but do infect other cells (98). When 4T1 murine tumors became palpable, SFV vectors were injected i.t., with a second dose administered six days later.…”

Section: Viral Gene Vectorsmentioning

confidence: 99%

Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies

Mantooth,

Abdou,

Saez-Ibañez

et al. 2024

Front. Immunol.

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Breast cancer poses one of the largest threats to women’s health. Treatment continues to improve for all the subtypes of breast cancer, but some subtypes, such as triple negative breast cancer, still present a significant treatment challenge. Additionally, metastasis and local recurrence are two prevalent problems in breast cancer treatment. A newer type of therapy, immunotherapy, may offer alternatives to traditional treatments for difficult-to-treat subtypes. Immunotherapy engages the host’s immune system to eradicate disease, with the potential to induce long-lasting, durable responses. However, systemic immunotherapy is only approved in a limited number of indications, and it benefits only a minority of patients. Furthermore, immune related toxicities following systemic administration of potent immunomodulators limit dosing and, consequently, efficacy. To address these safety considerations and improve treatment efficacy, interest in local delivery at the site of the tumor has increased. Numerous intratumorally delivered immunotherapeutics have been and are being explored clinically and preclinically, including monoclonal antibodies, cellular therapies, viruses, nucleic acids, cytokines, innate immune agonists, and bacteria. This review summarizes the current and past intratumoral immunotherapy clinical landscape in breast cancer as well as current progress that has been made in preclinical studies, with a focus on delivery parameters and considerations.

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Section: Viral Gene Vectorsmentioning

confidence: 99%

Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies

Mantooth,

Abdou,

Saez-Ibañez

et al. 2024

Front. Immunol.

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Recombinant Viral Vectors for Therapeutic Programming of Tumour Microenvironment: Advantages and Limitations

2022

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Viral vectors have been widely investigated as tools for cancer immunotherapy. Although many preclinical studies demonstrate significant virus-mediated tumour inhibition in synergy with immune checkpoint molecules and other drugs, the clinical success of viral vector applications in cancer therapy currently is limited. A number of challenges have to be solved to translate promising vectors to clinics. One of the key elements of successful virus-based cancer immunotherapy is the understanding of the tumour immune state and the development of vectors to modify the immunosuppressive tumour microenvironment (TME). Tumour-associated immune cells, as the main component of TME, support tumour progression through multiple pathways inducing resistance to treatment and promoting cancer cell escape mechanisms. In this review, we consider DNA and RNA virus vectors delivering immunomodulatory genes (cytokines, chemokines, co-stimulatory molecules, antibodies, etc.) and discuss how these viruses break an immunosuppressive cell development and switch TME to an immune-responsive “hot” state. We highlight the advantages and limitations of virus vectors for targeted therapeutic programming of tumour immune cell populations and tumour stroma, and propose future steps to establish viral vectors as a standard, efficient, safe, and non-toxic cancer immunotherapy approach that can complement other promising treatment strategies, e.g., checkpoint inhibitors, CAR-T, and advanced chemotherapeutics.

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Fibronectin Functions as a Selective Agonist for Distinct Toll-like Receptors in Triple-Negative Breast Cancer

Ambesi

Maddali

McKeown‐Longo

2022

Cells

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The microenvironment of tumors is characterized by structural changes in the fibronectin matrix, which include increased deposition of the EDA isoform of fibronectin and the unfolding of the fibronectin Type III domains. The impact of these structural changes on tumor progression is not well understood. The fibronectin EDA (FnEDA) domain and the partially unfolded first Type III domain of fibronectin (FnIII-1c) have been identified as endogenous damage-associated molecular pattern molecules (DAMPs), which induce innate immune responses by serving as agonists for Toll-Like Receptors (TLRs). Using two triple-negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231, we show that FnEDA and FnIII-1c induce the pro-tumorigenic cytokine, IL-8, by serving as agonists for TLR5 and TLR2, the canonical receptors for bacterial flagellin and lipoprotein, respectively. We also find that FnIII-1c is not recognized by MDA-MB-468 cells but is recognized by MDA-MB-231 cells, suggesting a cell type rather than ligand specific utilization of TLRs. As IL-8 plays a major role in the progression of TNBC, these studies suggest that tumor-induced structural changes in the fibronectin matrix promote an inflammatory microenvironment conducive to metastatic progression.

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Alphavirus-driven Interferon Gamma (IFNg) Expression Inhibits Tumour Growth in Orthotopic 4T1 Breast Cancer Model

Cited by 9 publications

References 98 publications

Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies

Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies

Recombinant Viral Vectors for Therapeutic Programming of Tumour Microenvironment: Advantages and Limitations

Fibronectin Functions as a Selective Agonist for Distinct Toll-like Receptors in Triple-Negative Breast Cancer

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