Research progress in the mechanism of abscopal effect induced by radiation / 中华放射肿瘤学杂志

Radiotherapy combined with immunotherapy for the treatment of cancer can induce stronger abscopal effect (AE) and inhibit the growth of tumors outside of radiation field, but the occurrence of AE is distinctly uncommon and unpredictable in clinical practice. The complex molecular mechanism underlying AE remains to be in-depth understood. It has been reported that some new factors are involved in the regulation of AE induced by radiation, but the molecular mechanism has not been fully unravelled. In this article, the roles of macrophages, tumor draining lymph node, p53 and exosomes in the new mechanisms of AE were reviewed, aiming to provide a theoretical basis for the development of more effective cancer therapeutics.

Advancements in the research of immunomodulatory effects of radiation therapy:from basic to clinical / 中国癌症杂志

Previously,radiotherapy was considered to directly kill tumor cells by deoxyribonucleic acid double-strand break.Recent studies have found that radiotherapy can also produce positive and effective anti-tumor effect by upregulating local and systemic immune responses.However,the immunomodulatory effect of radiotherapy is double-sided.On the one hand,it can activate anti-tumor immune-promoting effect,on the other hand,it may also produce immunosuppressive effect.The key molecular mechanisms of the positive regulation of adaptive and innate anti-tumor response by radiotherapy primarily include:induction of immunogenic cell death to promote the proliferation and activation of T lymphocytes;activation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway to induce type Ⅰ interferon response;changing the phenotype of tumor cells to enhance their immunogenicity and antigen visibility;stimulating tumor cells and stromal cells to release a variety of inflammatory factors and reshape the tumor immune microenvironment;upregulating the expression of immune checkpoint and death receptor on the surface of tumor cells to promote immune recognition and anti-tumor immune response.In addition,the mechanisms of negative immune suppression by radiotherapy mainly include:induction of tumor cells to upregulate the gene expression of multiple immunosuppressive factors;enhancing the function and effect of various immunosuppressive cells,including regulatory T cells and myeloid-derived suppressor cells;leading to the decreased number of lymphocytes and the depletion of immunologic effector cells.Based on the above exploration of the mechanisms and principle of the immunomodulatory effect of radiotherapy,significant progress has also been shown in the clinical practice of combining radiotherapy with immunotherapy,such as the abscopal effect in the context of immunotherapy era,that is,the effective anti-tumor immune responses generated outside the irradiation field of radiotherapy,as well as the increased efficacy benefit when stereotactic body radiation therapy or low-dose radiotherapy combined with immune checkpoint inhibitors.However,at present,the synergistic mechanism of radiotherapy plus immunotherapy and its influencing factors are unclear.In the future,more in-depth investigations on optimal radiotherapy dose,segmentation regimens,irradiation sites and target volume design,immunotherapy agent selection and the sequence of combining radiotherapy with immunotherapy are necessary,in order to further improve efficacy and promote the translational application of immunomodulatory biological effects of radiotherapy.This article systematically reviewed the latest advancements of basic and clinical research on the immunomodulatory effect of radiotherapy and the synergy of combing radiotherapy with immunotherapy,aiming to provide guidance on the development of theoretical basis and clinical practice regarding the combination of radiotherapy and immunotherapy.

Research advances in immune response of stereotactic body radiotherapy / 中华放射肿瘤学杂志

The mechanisms of radiotherapy (RT) in cancer treatment are both by immunity and non-immunity pathways. According to different absorbed doses, the immune modulating effect of RT comprises of tumor microenvironment modulating effect, immune-modulatory effect as well as immune-ablative effect. RT could improve the therapeutic efficacy of immunotherapy, while immunotherapy could enlarge the immunity activating effect induced by RT in turn. Therefore, RT is emerging as a valuable partner of cancer immunotherapy. RT regimens have a vital impact on immunity within tumor microenvironment. Stereotactic body RT (SBRT) has obvious advantages regarding interferon production and abscopal effect. At present, potentially sub-ablative RT regimen of 8 Gy plus 3 fractionations is the most widely used SBRT. Several novel RT regimens, such as hybrid fractionation, singular site irradiation and multisite irradiation, have been designed to maximize the immune induction effect and improve the combination efficacy with immunotherapy in metastatic malignancies. In this review, the latest advances in the immune effect of RT were discussed and novel SBRT regimens were proposed, aiming to provide reference for enhancing the efficacy of radio-immunotherapy or immuno-radiotherapy in clinical practice.

The roles and clinical controversies of radiotherapy and immunotherapy in abscopal effect / 中华放射肿瘤学杂志

As early as the 20 th century, it has been observed that radiotherapy (RT), as a local therapy, can activate the adaptive immune system, resulting in spontaneous regression of tumors out of the radiation field, which is known as "abscopal effect". Although the occurrence of abscopal effect is still rare, with the gradual increase in the application of immunotherapy, more and more clinical cases of abscopal effect have been reported. Increasing attention has been paid to the therapeutic potential of RT in inducing systemic anti-tumor response. Especially, the combination of RT and immunotherapy enhances the research value of abscopal effect. However, its mechanism has not been fully elucidated, and the optimal timing, dose and fractionation of RT are also under study. How to classify the beneficiary groups is also a key issue. In this article, the history of abscopal effect, and the role of RT and immunotherapy in this phenomenon were briefly introduced, and the existing controversies in clinical application were illustrated, aiming to clarify the direction of current research and development and open a new chapter for tumor treatment in a short period of time.

2-Hexyl-4-Pentylenic Acid (HPTA) Stimulates the Radiotherapy-induced Abscopal Effect on Distal Tumor through Polarization of Tumor-associated Macrophages / 生物医学与环境科学（英文）

Objective@#The aim of this study was to explore the effects of 2-hexyl-4-pentylenic acid (HPTA) in combination with radiotherapy (RT) on distant unirradiated breast tumors.@*Methods@#Using a rat model of chemical carcinogen (7,12-dimethylbenz[a]anthracene,DMBA)-induced breast cancer, tumor volume was monitored and treatment response was evaluated by performing HE staining, immunohistochemistry, immunofluorescence, qRT-PCR, and western blot analyses.@*Results@#The results demonstrated that HPTA in combination with RT significantly delayed the growth of distant, unirradiated breast tumors. The mechanism of action included tumor-associated macrophage (TAM) infiltration into distant tumor tissues, M1 polarization, and inhibition of tumor angiogenesis by IFN-γ.@*Conclusion@#The results suggest that the combination of HPTA with RT has an abscopal effect on distant tumors

Extracranial systemic antitumor response through the abscopal effect induced by brain radiation in a patient with metastatic melanoma

The abscopal effect is a term that has been used to describe the phenomenon in which localized radiation therapy treatment of a tumor lesion triggers a spontaneous regression of metastatic lesion(s) at a non-irradiated distant site(s). Radiation therapy induced abscopal effects are believed to be mediated by activation and stimulation of the immune system. However, due to the brain’s distinctive immune microenvironment, extracranial abscopal responses following cranial radiation therapy have rarely been reported. In this report, we describe the case of 42-year-old female patient with metastatic melanoma who experienced an abscopal response following her cranial radiation therapy for her brain metastasis. The patient initially presented with a stage III melanoma of the right upper skin of her back. Approximately 5 years after her diagnosis, the patient developed a large metastatic lesion in her upper right pectoral region of her chest wall and axilla. Since the patient’s tumor was positive for BRAF and MEK, targeted therapy with dabrafenib and trametinib was initiated. However, the patient experienced central nervous system (CNS) symptoms such as headache and disequilibrium and developed brain metastases prior to the start of targeted therapy. The patient received radiation therapy to a dose of 30 Gy delivered in 15 fractions to her brain lesions while the patient was on dabrafenib and trametinib therapy. The patient’s CNS metastases improved significantly within weeks of her therapy. The patient’s non-irradiated large extracranial chest mass and axilla mass also shrank substantially demonstrating the abscopal effect during her CNS radiation therapy. Following radiation therapy of her residual chest lesions, the patient was disease free clinically and her CNS lesions had regressed. However, when the radiation therapy ended and the patient continued her targeted therapy alone, recurrence outside of her previously treated fields was noted. The disease recurrence could be due to the possibility of developing BRAF resistance clones to the BRAF targeted therapy. The patient died eventually due to wide spread systemic disease recurrence despite targeted therapy.

Application mechanisms of radiotherapy combined with immune checkpoint inhibitors / 中华放射肿瘤学杂志

Remarkable advances have been made in immunotherapy,especially immune checkpoint inhibitors.However,only less than 30％ patients would respond to single checkpoint inhibitors.Radiotherapy can augment the anti-tumor immune responses elicited by immunotherapy,either by way of synergy or complementation.This article reviews the mechanisms,the advances and challenges in combination therapy.

Radiotherapy and immune response: the systemic effects of a local treatment

Technological developments have allowed improvements in radiotherapy delivery, with higher precision and better sparing of normal tissue. For many years, it has been well known that ionizing radiation has not only local action but also systemic effects by triggering many molecular signaling pathways. There is still a lack of knowledge of this issue. This review focuses on the current literature about the effects of ionizing radiation on the immune system, either suppressing or stimulating the host reactions against the tumor, and the factors that interact with these responses, such as the radiation dose and dose / fraction effects in the tumor microenvironment and vasculature. In addition, some implications of these effects in cancer treatment, mainly in combined strategies, are addressed from the perspective of their interactions with the more advanced technology currently available, such as heavy ion therapy and nanotechnology.

Recent research progress of abscopal effect in tumor radiotherapy / 中华放射医学与防护杂志

If loosely defined,an abscopal effect occurs when localized irradiation affects the whole organism.In recent years,distant tumor regression and normal tissue damage after localized irradiation have been concerned by immuno-oncologists.However,the mechanisms of this effect are still far from clear.Mounting evidences suggest that the generation of abscopal effects is closely related to immune regulation.Radiotherapy might become a systemic tumor-treatment modality by enhancing immune function and played an important role in every stage of tumor development and prognosis.For the moment,targeting the immune checkpoint has become an attractive approach for malignant tumor therapy.Preclinical data have revealed that a strong abscopal effect could be effectively induced by the co-treatement of immune checkpoint inhibitors and irradiation,which could recruit antitumor T cells and achieve a powerful antitumor effect.This review discusses current progress and perspectives of abscopal effects in the combination of radiotherapy and immunotherapy.

Biological foundation and research progress on radiotherapy combined with immuno-therapy / 中国肿瘤临床

Numerous studies revealed that radiation can promote the immunogenic cell death, enhance the immune response of tu-mor-antigen-specific T cells, and induce systematic antitumor immunity, which may result in abscopal effect. Abscopal effect refers to the regression of non-irradiated metastatic lesions distant from the primary tumor site that is directly subjected to irradiation. Despite that abscopal effect has been clinically reported and that many preclinical studies have confirmed its biological basis, abscopal effect remains a subclinical phenomenon, in which objective efficacy is difficult to obtain. Currently, the anti-PD-1/PD-L1 therapy in clinical applications shows a clear and definite curative effect, thereby making local radiotherapy combined with immunotherapy a new treat-ment pattern. However, the clinical practice of this new mode should be based on appropriate dose and fraction and the most suitable temporal combination to achieve the synergic antitumor immune response.

A Case of Abscopal Effect on Pulmonary Metastasis after Palliative Radiotherapy on Bone Metastasis of Hepatocellular Carcinoma

The abscopal effect is a rare phenomenon that characterized by tumor regression of untreated metastatic lesions after a local radiotherapy. The mechanisms of abscopal effect are speculated to be associated with cytokine release and host immune system. In this case, we report a case of abscopal effect in a 64-year-old male with hepatocellular carcinoma with lung and bone metastasis, who had complete response in the lung after receiving radiation to the metastatic bone lesions.