Post-irradiation induces abscopal effect, how does it occur?
Post-irradiation induces abscopal effect, how does it occur?
Hossein Azadinejad,1,*Mohammad Farhadi Rad,2Mahmood Mohammadi Sadr,3Mahboobeh soleimanpoor,4Mohammad Ghaderian,5
1. Department of immunology, school of medicine, Kermanshah university of medical sciences , Kermanshah,Iran 2. Department of Radiology and nuclear medicine, School of paramedical, Kermanshah University of Medical Sciences, Kermanshah, Iran 3. Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran 4. Department of Radiology Technology, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 5. Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Introduction: For more than a century, radiotherapy has been utilized to treat local tumors. Radiation therapy(RT) breaks the DNA and causes cancer cells to die. Radiotherapy often affects uses to Impact the proliferation of tumors at the targeted spot. Nevertheless, there have been instances of cell death outside of the targeted areas. The ability of concentrated radiation to trigger an anticancer response across the body at locations that were not exposed to directed RT is known as the abscopal effect. This phenomenon was introduced by R.H.Mole in the early 1950s. The exact mechanisms of the abscopal effect are not fully understood. The goal of this article is to shed light on possible mechanisms and pave the path for future research (1, 2).
Methods: To conduct this review, we searched Pubmed, Scopus, and Google scholar databases using the keyword "Abscopal effect" AND” Radiotherapy” and selected the latest related articles.
Results: Historically, RT was thought to suppress the immune system because lymphocytes are some of the radiosensitive cells. Although, several pre-clinical and clinical research backs the idea that the immune system is involved in the spontaneous shrinkage of tumors beyond the irradiated region. Pre-clinical experiments have now demonstrated that RT can improve MHC class I levels and the antigen-processing and presentation pathway.MHC class I is involved in the activation of CD8+ T cells, which are the most important tumor-killing cells. Apparently, RT's abscopal effects depend on CD8+ T cells. It has been shown that radiotherapy can cause DNA damage in almost two ways:1- direct DNA break which is due to the high energy electrons and 2-development of free radicals that can result in indirect DNA damage. The most fatal kind of DNA damage is double-strand breaks (DSBs), which are brought on by RT. DSBs can reveal double-stranded DNA (dsDNA) to the cytoplasmic dsDNA sensor cyclic GMP-AMP synthase (cGAS) which in turn, cGAS induces type I interferon production by the downstream stimulator of IFN genes (STING). Type I IFN released by irradiated cells is necessary for RT to elicit the abscopal effect effectively. According to recent investigations, particular types of programmed cell death, like necroptosis and immunogenic cell death (ICD), are induced by RT. Both ICD and necroptosis can lead to the release of damage-associated molecular patterns (DAMPs) from irradiated cells. DAMPs such as HMGB1, HSP, membrane-exposed calreticulin, and glucose-regulated protein 96(GP96) can enhance antigen presentation by dendritic cells and induce phagocytosis of tumor cells. These events cause the maturation of dendritic cells and lead to boosted T CD8+ cell-mediated tumor lysis. The adaptive anti-tumor immune response can function both independently and in conjunction with the innate immune system. For instance, human neutrophils can secret neutrophil elastase to particularly kill tumor cells (3, 4).
It is believed that mechanisms through which RT improves ICI are either or both proliferation and differentiation of naive T cells or the revitalization of exhausted intra-tumoral CD8+ T cells. Nowadays, monoclonal antibodies (mAb) that stimulate the immune system have already been coupled with RT and, in some cases, had an abscopal effect (4).
Conclusion: As mentioned above, both RT alone and RT in combination with immunostimulatory monoclonal antibodies (such as anti-CTLA-4 mAb, and anti-PD-1 mAb) generated an abscopal effect. Pre-clinical research demonstrates that in a range of animal models, ICI compounds, and RT changes lead to a range of responses. The best radiation dosage to elicit the abscopal effect has generated debate; some support single, ablative radiation doses, while others advocate for fractionation plans.
Barsoumian et al. showed that the RadScopal methodology, which combines high-dose and low-dose radiation therapy with immunotherapy, can be used to produce the abscopal effect. In this technique high-dose RT is administered to primary tumors to kill cancerous cells, reveal neoantigens, and stimulate T lymphocytes, while delivering low-dose RT to secondary tumors modifies the tumor stroma by inhibiting TGF-ß, allowing the infiltration and growth of effector T cells and natural killer cells.
However, the abscopal effect is not just limited to RT.especialy in renal cancer, the abscopal effect has been seen after surgical resection of the primary tumor. Although the main reason for this is not fully understood, the possible reasons are that Surgery to remove the primary tumor lowers the tumor burden and makes it possible for the immune system to successfully remove any leftover cells or Surgery may systemically expose tumor antigens, exposing T lymphocytes to the appropriate antigen repertoire.
Despite the promising results obtained from the studies, the abscopal effect is a complex and unpredictable phenomenon, and more research is needed to fully understand the mechanisms involved in this phenomenon (1-4).