Immunomodulatory Mechanisms of Oncolytic Virus Therapy
Oncolytic Virus-the Most Watched Tumor Immunotherapy
At the end of the 19th century, a woman with leukemia suddenly recovered after a suspected infection with influenza virus, and in 1912, an Italian doctor also reported a case in which patients with advanced cervical cancer had a significant remission after injection of rabies vaccine. These cases led to the strategy of using oncolytic viruses to treat tumors in a "combat poison with poison" manner. Oncolytic viruses are natural or artificially engineered viruses that can selectively replicate in tumor tissues, thereby killing tumor cells, but have no killing effect on normal tissues. In addition to directly killing tumor cells, oncolytic viruses can induce a strong immune response, can participate in multiple stages of anti-tumor immunity, exert their anti-tumor activity and enhance the body's anti-tumor responses. Nowadays, oncolytic viruses have become one of the most interesting cancer therapies, and have broad application prospects in the future immune combination therapy. Oncolytic virus construction and oncolytic virus engineering and have become promising strategies for cancer treatment.
Immunomodulatory Mechanisms of Oncolytic Virus Therapy
T cells need to go through four key steps in order to initiate a successful anti-tumor response. Oncolytic viruses have the advantages of specific targeting selectivity to tumor cells and increase the strength of the body's immune response, and can assist T cells in these four steps.
- T Cell Priming
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Trafficking and Infiltration
The circulating T cells can move to the tumor site for infiltration, which is of great significance to the prognosis of patients. The use of oncolytic viruses is expected to enhance the infiltration of T cells into tumors. There are many potential mechanisms behind this:
- Viral infection can stimulate a potential class I interferon response, stimulate chemokine production, and recruit T cells. Animal experiments have found that whether it is adenovirus, HSV-1, vaccinia virus or Newcastle disease virus can effectively increase T cell infiltration. In addition, clinical trials have also confirmed that in melanoma and other advanced cancer types, oncolytic viruses can increase T cell infiltration.
- Oncolytic viruses can induce TNF, IL-1β, and complement responses, up-regulate the expression of selectin on endothelial cells, and provide a key signal for T cell infiltration.
- By transforming oncolytic viruses, it is expected to achieve regulation of specific oncogenic signaling pathways. For example, the WNT-β-catenin pathway has an immunosuppressive effect, and it is able to maintain the cell's antiviral response. After modification, many oncolytic viruses can be activated by β-catenin signaling pathway, thereby promoting tumor-specific virus replication and anti-tumor effects.
- Oncolytic viruses can encode T cell chemotactic factor, making it possible to directly recruit T cells without worrying about the defective expression of chemokines in the tumor environment. Moreover, the study also pointed out that oncolytic viruses can also help overcome organizational structural obstacles, such as by attracting neutrophils to release inflammatory mediators and proteases with cytotoxicity and extracellular matrix degradation in the tumor microenvironment to further aid in T cell infiltration.
- Circumventing Immune Suppression
- Engagement of Tumor Cells
The initiation of the T cell response first requires the recognition of specific epitopes. This complex process requires antigen-presenting cells to achieve. In cancer, antigen presentation is often negatively regulated, causing the tumor to "cold down" immunologically. Oncolytic viruses can achieve a vaccine-like effect, that is, to promote the presentation and recognition of tumor-associated antigens. Local oncolytic virus treatment can lyse cancer cells, release a large number of tumor-associated antigens, and create an immuno-friendly cytokine environment, thereby facilitating antigen-presenting cells to achieve their functions. The experiment found that the chimerism of poliovirus and rhabdovirus can lead to the release of tumor antigens and produce a type I interferon response. These stimuli will eventually induce the proliferation of tumor-specific T cell populations.
The successful infiltration of T cells in the tumor does not mean that they can effectively attack the tumor, but still need to overcome immunosuppressive molecules such as IL-10, TGF β, and IDO in the tumor environment. The oncolytic virus has the ability to induce pro-inflammatory helper T cells 1 to change the inhibitory tumor microenvironment, turning "cold tumors" into "hot tumors".
The last step of successful immunotherapy lies in the recognition, combination and attack of tumor cells by T cells. Tumor cells can avoid T cell recognition by down-regulating the pathways involved in antigen presentation and MHC-I molecules. Oncolytic viruses are expected to achieve a certain degree of reversal in this respect. For example, reovirus can increase the expression of MHC-I or MHC-II on tumor cells and antigen-presenting cells. In addition, tumor cells infected with HSV can also promote the maturation of dendritic cells and the expression of MHC-II.
Creative Biolabs is committed to the development and evaluation of cancer immunotherapy based on oncolytic viruses, especially for disease-specific oncolytic virotherapy development. In this regard, extensive and in-depth research has been carried out and a series of high-quality services and products have been launched.