Virus-Like Particles for TEM Regulation against Cancer

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Zhu Yang	--	1145	2023-02-17 02:02:05	\|
2	format correct	Catherine Yang	Meta information modification	1145	2023-02-17 02:07:03	\|

This entry is adapted from the peer-reviewed paper 10.3390/jfb13040304

Tumor development and metastasis are intimately associated with the tumor microenvironment (TME), and it is difficult for vector-restricted drugs to act on the TME for long-term cancer immunotherapy. Virus-like particles (VLPs) are nanocage structures self-assembled from nucleic acid free viral proteins. Most VLPs range from 20–200 nm in diameter and can naturally drain into lymph nodes to induce robust humoral immunity. As natural nucleic acid nanocarriers, their surfaces can also be genetically or chemically modified to achieve functions such as TME targeting.

virus-like particle tumor microenvironment immunotherapy nanovaccine

1. Targeting Dendritic Cells

Tumor-infiltrating DCs, as the first step in the anti-tumor immune response, tend to exhibit quantitative and functional defects in TME due to oncometabolites and tumor-derived suppressors ^[1]^[2]. To regulate their specific activation and maturation, DCs are usually targeted with VLPs that are co-loaded with antigens and coupled to specific ligands, like CD40, CD11c, CD205, or mannose receptor. Alam et al. ^[3] biocoupled different aryl mannose to Qβ-VLP to enable uptake via DC-SIGN. The results showed that Qβ-Man was only selectively taken up by DC-SIGN expressing cell lines and efficiently delivered to the endosomal compartments for DC maturation and expression of pro-inflammatory cytokines such as IL-1β. Miraculously, targeting different subpopulations of DC cells may also produce different therapeutic effects. Li et al. ^[4] found that recombinant VLP-gp33r was more effective than conjugated VLP-gp33c when used as a therapeutic vaccine because the former affected the induction of cytotoxic effector cells via Langerin⁺ DC. Incidentally, in addition to specifically targeting DC cells, some studies have looked at DC activation and maturation through the encapsulation of DC activating molecules by VLPs. Gomes et al. ^[5] fabricated the Qβ-E7-Cpg to ensure that DCs were properly activated through dual stimulation. Alternatively, vaccine efficacy can be increased by altering the delivery strategy, for example by intradermal administration through gene gun, laser treatment after intradermal injection, and electroporation after intramuscular injection ^[6]. Guo et al. ^[7] prepared microneedle patches containing OVA-HBc VLPs and mesoporous silica nanoparticles that could achieve 42% BMDC maturation in vitro to induce CD8⁺ T cell-mediated immune responses. With the characteristics of DCs, the delivery of antigens by VLPs has become the most fundamental and widespread design strategy. Specifically targeting DCs is effective in avoiding systemic toxicity or autoimmunity of nano-agents, but also therefore requires accurate antigens and appropriate dosage. Meanwhile, the functions of different DC subpopulations need to be studied in more depth to achieve the most appropriate formulation.

2. Targeting Tumor-Associated Macrophages

While most TAMs originate from monocytic precursors, recent studies have shown that tissue-resident macrophages (TRMs) originate from embryonic precursors and may maintain TAM levels ^[8]. As typical plastic cells, TAMs can undergo various forms of phenotypic polarization upon stimulation by different microenvironmental signals. From the perspective of cancer vaccine design, TAM are often simply divided into classically activated or inflammatory (M1) and alternatively activated or anti-inflammatory (M2) macrophages, depending on the expression of cell surface markers and their biological function. In response to hypoxia and changes in cytokines such as IL-4 in the TME, TAM1 repolarises to TAM2 to promote immunosuppression. For example, immune checkpoint ligands with elevated levels of TAM expression, such as PD-L1, PD-L2, etc., thereby directly inhibit T-cell activity ^[9].

Further, the utilization of VLPs to specifically deliver drugs to TAM and modulate phenotype reversal is a viable idea for cancer vaccines. For example, CpG-ODNs can promote M1 polarization in macrophages via TLR9. Cai et al. ^[10] used the disassembly and reassembly of CCMV to package ODN1826, which could significantly improve drug efficiency. Recombinant VLP is preferentially taken up by TAM and promotes M1 polarization, thereby enhancing the therapeutic effect on colon cancer and melanoma in mice. Given their small size and ability to cross physiological barriers, VLPs enable multiple modes of delivery to modulate the TME. Zhang et al. ^[11] loaded antigen and adjuvant via OVA-HBc-Poly (I:C) while compounding immunomodulator-containing (JQ1) liposomes for endotracheal administration in the lung. The results showed that the nanovaccine promoted M1 polarization, significantly reduced PD-L1 expression levels in the tumor-bearing lung, enhanced CTL response, and reshaped the tumor microenvironment. For clinical applications, the most practical approach remains to explore therapeutic strategies in combination with conventional therapies to achieve tumor suppression. An example is tumor regression after radiotherapy which can recruit inflammatory cells and can be followed by the addition of CMP-001 (Qβ-CpG) to activate a sustained anti-tumor effect ^[12].

Strategies to target TAM also include small molecule drugs such as Bruton’s tyrosine kinase (BTK) to inhibit TAM survival and function, but unfortunately there has not been more in-depth research in VLPs vectors ^[13]. Similarly, TAM of different origins, such as systemically recruited or tissue-resident, have different treatment outcomes. VLPs still have substantial unexplored advantages in targeting TAMs, such as the fusion of protein-like receptors such as M2-targeting peptides (M2pep) to VLPs for expression, or the loading of VLPs with other small molecule drugs. Ultimately, it is hoped that with a better understanding of TAMs and VLPs, nanovaccines will provide more ideas for tumor immunotherapy.

3. Targeting Tumor-Infiltrating Treg Cells

Although a variety of immunosuppressive T cells have been identified and studied, such as CD4⁺ type 1 T regulatory (Tr1) cells ^[14], the vast majority in the tumor microenvironment are still Treg cells (CD4⁺ CD25⁺ Foxp3⁺). Treg cells affect the normal work of responding T cells by binding with high affinity to IL-2 in the environment, while high expression of IL-10 and CTLA-4 inhibits CD80/CD86 expression in APCs and thus indirectly inhibits T cell co-stimulatory activation. Therefore cancer immunotherapy targeting Treg cells should choose molecules that are relatively specific to Treg depletion or functional regulation, such as CTLA-4, PD-1, OX-40, etc. ^[15]. Agonistic antibodies that antagonize Treg-mediated immunosuppression and activate T-cell proliferation can be selected to modify VLP. For example, Palameta et al. ^[16] generated 4-1BBL + OX40L bivalent VLP that significantly reduced the transformation of FoxP3-positive cells and increased T-cell proliferation and IFN-γ secretion. The PSMA ligand is then simultaneously attached for tumor cell targeting and anchored to GM-CSF for tumor targeting and stimulation of DCs differentiation. Another idea is to use checkpoint blocking antibodies that deplete the effect of Treg. Whether coupled to a PD-1 antibody or in combination therapy, the VLP vector usually requires T cell stimulator modification to better stimulate CD8⁺ T activation. Simons et al. ^[17] modified VLP with prostate cancer-associated tumor antigens and T-cell stimulators, and both the vaccine alone and the anti-PD1 antibody combination significantly reduced tumor load. Targeted Treg immunotherapy is usually accompanied by autoimmune side effects. Therefore, whether VLP or other carriers are used, the effector Treg in tumor tissue should be selectively targeted, and the dose and time should be adjusted to achieve the balance between tumor immunity and autoimmune.

Of course, there are also some studies targeting other TME components with VLP as a carrier, such as vascular venation ^[18]. However, due to the lack of systematic research, it is not discussed here.

References

Lee, J.-H.; Choi, S.-Y.; Jung, N.-C.; Song, J.-Y.; Seo, H.G.; Lee, H.S.; Lim, D.-S. The Effect of the Tumor Microenvironment and Tumor-Derived Metabolites on Dendritic Cell Function. J. Cancer 2020, 11, 769–775.
Zhu, S.; Yang, N.; Wu, J.; Wang, X.; Wang, W.; Liu, Y.-J.; Chen, J. Tumor Microenvironment-Related Dendritic Cell Deficiency: A Target to Enhance Tumor Immunotherapy. Pharmacol. Res. 2020, 159, 104980.
Alam, M.M.; Jarvis, C.M.; Hincapie, R.; McKay, C.S.; Schimer, J.; Sanhueza, C.A.; Xu, K.; Diehl, R.C.; Finn, M.G.; Kiessling, L.L. Glycan-Modified Virus-like Particles Evoke T Helper Type 1-like Immune Responses. ACS Nano 2021, 15, 309–321.
Li, K.; Peers-Adams, A.; Win, S.J.; Scullion, S.; Wilson, M.; Young, V.L.; Jennings, P.; Ward, V.K.; Baird, M.A.; Young, S.L. Antigen Incorporated In Virus-like Particles Is Delivered to Specific Dendritic Cell Subsets That Induce An Effective Antitumor Immune Response In Vivo. J. Immunother. 2013, 36, 11–19.
Gomes, A.C.; Flace, A.; Saudan, P.; Zabel, F.; Cabral-Miranda, G.; Turabi, A.E.; Manolova, V.; Bachmann, M.F. Adjusted Particle Size Eliminates the Need of Linkage of Antigen and Adjuvants for Appropriated T Cell Responses in Virus-Like Particle-Based Vaccines. Front. Immunol. 2017, 8, 226.
Lin, K.; Roosinovich, E.; Ma, B.; Hung, C.-F.; Wu, T.-C. Therapeutic HPV DNA Vaccines. Immunol. Res. 2010, 47, 86–112.
Wang, C.; Ye, Y.; Hochu, G.M.; Sadeghifar, H.; Gu, Z. Enhanced Cancer Immunotherapy by Microneedle Patch-Assisted Delivery of Anti-PD1 Antibody. Nano Lett. 2016, 16, 2334–2340.
Mantovani, A.; Allavena, P.; Marchesi, F.; Garlanda, C. Macrophages as Tools and Targets in Cancer Therapy. Nat. Rev. Drug Discov. 2022, 21, 799–820.
Umezu, D.; Okada, N.; Sakoda, Y.; Adachi, K.; Ojima, T.; Yamaue, H.; Eto, M.; Tamada, K. Inhibitory Functions of PD-L1 and PD-L2 in the Regulation of Anti-Tumor Immunity in Murine Tumor Microenvironment. Cancer Immunol. Immunother. 2019, 68, 201–211.
Cai, H.; Shukla, S.; Steinmetz, N.F. The Antitumor Efficacy of CpG Oligonucleotides Is Improved by Encapsulation in Plant Virus-Like Particles. Adv. Funct. Mater. 2020, 30, 1908743.
Zhang, X.; Zhang, Y.; Zheng, H.; He, Y.; Jia, H.; Zhang, L.; Lin, C.; Chen, S.; Zheng, J.; Yang, Q.; et al. In Situ Biomimetic Nanoformulation for Metastatic Cancer Immunotherapy. Acta Biomater. 2021, 134, 633–648.
Younes, A.I.; Barsoumian, H.B.; Sezen, D.; Verma, V.; Patel, R.; Wasley, M.; Hu, Y.; Dunn, J.D.; He, K.; Chen, D.; et al. Addition of TLR9 Agonist Immunotherapy to Radiation Improves Systemic Antitumor Activity. Transl. Oncol. 2021, 14, 100983.
Weber, A.N.R.; Bittner, Z.; Liu, X.; Dang, T.-M.; Radsak, M.P.; Brunner, C. Bruton’s Tyrosine Kinase: An Emerging Key Player in Innate Immunity. Front. Immunol. 2017, 8, 1454.
Gagliani, N.; Magnani, C.F.; Huber, S.; Gianolini, M.E.; Pala, M.; Licona-Limon, P.; Guo, B.; Herbert, D.R.; Bulfone, A.; Trentini, F.; et al. Coexpression of CD49b and LAG-3 Identifies Human and Mouse T Regulatory Type 1 Cells. Nat. Med. 2013, 19, 739–746.
Tanaka, A.; Sakaguchi, S. Regulatory T Cells in Cancer Immunotherapy. Cell Res. 2017, 27, 109–118.
Palameta, S.; Manrique-Rincón, A.J.; Toscaro, J.M.; Semionatto, I.F.; Fonseca, M.C.; Rosa, R.S.M.; Ruas, L.P.; Oliveira, P.S.L.; Bajgelman, M.C. Boosting Antitumor Response with PSMA-Targeted Immunomodulatory VLPs, Harboring Costimulatory TNFSF Ligands and GM-CSF Cytokine. Mol. Ther.-Oncolytics 2022, 24, 650–662.
Simons, B.W.; Cannella, F.; Rowley, D.T.; Viscidi, R.P. Bovine Papillomavirus Prostate Cancer Antigen Virus-like Particle Vaccines Are Efficacious in Advanced Cancers in the TRAMP Mouse Spontaneous Prostate Cancer Model. Cancer Immunol. Immunother. 2020, 69, 641–651.
Yang, J.; Zhang, Q.; Liu, Y.; Zhang, X.; Shan, W.; Ye, S.; Zhou, X.; Ge, Y.; Wang, X.; Ren, L. Nanoparticle-Based Co-Delivery of SiRNA and Paclitaxel for Dual-Targeting of Glioblastoma. Nanomedicine 2020, 15, 1391–1409.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Engineering, Biomedical

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Zhu Yang

Yongjie Chi

Jiaxin Bao

Xin Zhao

Jing Zhang

Lianyan Wang

View Times: 322

Entry Collection: Biopharmaceuticals Technology

Update Date: 17 Feb 2023

Table of Contents

Video Upload Options

Confirm

1. Targeting Dendritic Cells

2. Targeting Tumor-Associated Macrophages

3. Targeting Tumor-Infiltrating Treg Cells

References