Oncolytic Viruses Inflame the TME

Oncolytic or "cancer-killing" viruses (OVs) are a class of self-replicating immunotherapeutic agents that uses viruses to infect and destroy cancer cells. Their antitumor effects include direct tumor-selective oncolysis, as well as activation of host systemic innate and adaptive immune responses resulting in the recruitment of diverse immune cell types, including lymphocytes, into the tumor microenvironment (TME). OVs are increasingly considered appealing therapeutic agents. Although numerous naturally occurring OVs exist, genetically modifying OVs creates new cancer therapeutics to let them replicate only in transformed cells.

Mechanisms of OVs Therapy

OVs mediate tumor cell destruction by two main mechanisms: direct lysis of infected cells (oncolysis) and indirect augmentation of host antitumor immunity. These specific functions mainly include:

• OVs can selectively infect tumor cells resulting in tumor cells specific lysis and release of numerous molecules, including pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs), and tumor-associated antigens (TAAs).
• Inflammatory cytokines and chemokines are produced under OV infection, leading to the recruitment of innate immune cells. While OVs spread can be limited by the generation of antiviral immune responses, the initial local tumor cell killing can reverse the immunosuppressive TME, resulting in more effective release of TAAs, cross-presentation, and antitumoral effector T cell recruitment.
• Stroma degradation: various extracellular matrix (ECM)-degrading agents expressed by engineered OVs induce stroma degradation. Concurrently, OV-induced CAF lysis also inhibits excessive ECM production. Alleviated stroma fibrosis subsequently promotes the infiltration of T cells.
• OVs also target endothelial cells and tumor vasculature, leading to infection and lysis of endothelial cells, and more necrotic death of cancer cells due to disruption of tumor vasculature.

Fig.1 Mechanism of OVs targeting the TME.^1,3

Tumor Immune Microenvironment Remodeling by OVs

OVs can stimulate the immune system which is recruited into the tumor, skewing the neoplastic mass from an immuno-suppressive environment to an inflammatory site and mediating the conversion of "cold" tumors into "hot" tumors.

Fig.2 Oncolytic virotherapy process the ability to remodel the tumor immune microenvironment.^2,3

• Recruitment and activation of dendritic cells (DCs)

After OV infection, the innate immune system rapidly recognizes virus particles and promotes DC maturation. DCs can deliver OVs to the TME aiding OV-mediated oncolysis and the generation of anti-tumor immunity; while OVs can overturn impaired antigen presentation of DCs, promote DC maturation, and recruit more immune cells to the TME.

• Recruitment and activation of T Cells

OVs possess the capacity to enhance T cell activation. Mature dendritic cells will present tumor-associated and virus antigens to local and distant T cells. Concurrently, the ongoing virus infection attracts T cells to the tumor site. These responses also shift tumors from cold (immune desert) to hot (inflamed) tumors, thereby allowing cytotoxic T cells to infiltrate the TIME and perform tumor cell killing.

• Recruitment and activation of natural killer cells (NKs)

NK cells are activated and participate in tumor clearance following OV infection. OVs tackle the exclusion of NK cells from the TME, by increasing the production of chemokines that promote NK cell recruitment in the TME. In addition, OVs directly increase the susceptibility of cancer cells to NK killing by modulating the expression of activating and inhibitory NK ligands in cancer cells.

• Overcoming immune suppression

OVs are beneficial to induce polarization of tumor-associated macrophages (TAMs) toward M1 type together with the expression of proinflammatory cytokines, but the mechanisms remain uncertain. The generation of an antitumor immune response mediated by OVs infection also counteracts the immune suppression associated with Tregs and MDSCs.

Diversity of OVs

Today, many OVs platforms such as adenoviruses, herpes viruses, measles viruses, coxsackieviruses, polioviruses, picornavirus, reoviruses, poxviruses, vaccinia virus, and Newcastle disease viruses, are under preclinical and clinical development for cancer therapy. In addition to natural OVs, many genetically modified OVs with enhanced tumor targeting, antitumor efficacy, and safety have been generated.

With the help of our professional scientists, Creative Biolabs is committed to providing Oncolytic Virus Therapy Development services to accelerate the discovery, development, and manufacturing of your OV therapies. To date, we have already established a specified oncolytic virus construction process for different kinds of species. We offer many genetically modified OVs to meet your custom needs, such as cytokine/chemokine-expressing OVs, antibody-expressing OVs, immune checkpoint inhibitor-expressing OVs, etc. Our services include but not limited to:

• Oncolytic virus engineering
• Oncolytic virus construction
• Oncolytic virus in vitro validation study
• Oncolytic virus in vivo preclinical study
• Disease-specific oncolytic virotherapy development

References

1. Zhang, Yalei, et al. "Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy." Cancer Cell International 21.1 (2021): 262.
2. Zhang, Bin, Xilei Wang, and Ping Cheng. "Remodeling of tumor immune microenvironment by oncolytic viruses." Frontiers in Oncology 10 (2021): 561372.
3. Distributed under Open Access license CC BY 4.0, without modification.