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The Abscopal Effect of Radiation Therapy: What Is It and How Can We Use It in Breast Cancer?

ABSTRACT: The abscopal effect refers to the ability of localized radiation to trigger systemic antitumor effects. Over the past 50 years, reports on the abscopal effect arising from conventional radiation have been relatively rare. However, with the continued development and use of immunotherapy strategies incorporating radiotherapy with targeted immunomodulators and immune checkpoint blockade, the abscopal effect is becoming increasingly relevant in less immunogenic tumors such as breast cancer. Here, we review the mechanism of the abscopal effect, the current preclinical and clinical data, and the application of the abscopal effect in designing clinical trials of immunotherapy combined with radiotherapy in breast cancer.

SUBMITTER: Hu ZI

PROVIDER: S-EPMC5346418 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The Abscopal Effect of Radiation Therapy: What Is It and How Can We Use It in Breast Cancer?

Hu Zishuo I ZI McArthur Heather L HL Ho Alice Y AY

Current breast cancer reports 20170302 1

The abscopal effect refers to the ability of localized radiation to trigger systemic antitumor effects. Over the past 50 years, reports on the abscopal effect arising from conventional radiation have been relatively rare. However, with the continued development and use of immunotherapy strategies incorporating radiotherapy with targeted immunomodulators and immune checkpoint blockade, the abscopal effect is becoming increasingly relevant in less immunogenic tumors such as breast cancer. Here, we ...[more]

PMID: 28344743

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Systemic benefit of radiation therapy <i>via</i> abscopal effect.

Project description:Evidence of a systemic response related to localized radiation therapy (RT) in cancer management is rare. However, enhancing the immune response via immunotherapy followed by localized RT has shown evidence of tumor shrinkage to non-irradiated metastatic disease thereby inducing an "abscopal effect." Combined induction of the cGAS-STING pathway and activation of IFN-gamma signaling cascade related to RT within an activated immune environment promotes neoantigen presentation and expansion of cytotoxic effector cells enabling enhancement of systemic immune response. A proposed mechanism, case examples, and clinical trial evidence of "abscopal effect" benefit are reviewed. Results support strategic therapeutic testing to enhance "abscopal effect."

| S-EPMC9641206 | biostudies-literature

Macrophage-mediated abscopal effects of radiation therapy

Project description:Radiation therapy is a mainstay of cancer treatment, with more than 50% of all cancer patients receiving radiation during the course of their disease. Tumor irradiation can activate both innate and adaptive immune responses, and these responses can be pro- or anti-tumor growth . These observations have led to the search for antitumor approaches combining radiotherapy and specific immunotherapies, most commonly strategies promoting the systemic activation of T cells. Thus far, however, many cancer patients still suffer from local recurrence and/or untreatable metastatic disease after radiotherapy. Here we combine radiotherapy with activation of macrophage-mediated phagocytosis via blockade of the ?don?t-eat-me? cell surface molecule CD47 in small-cell lung cancer (SCLC), a highly metastatic form of lung cancer for which treatment options remain limited. We found that irradiation of SCLC cells in culture results in the secretion of inflammatory cytokines that results in increased migration and phagocytosis by macrophages. In vivo, CD47 blockade potently enhances the local antitumor effects of radiation therapy in murine and human pre-clinical models of SCLC. Strikingly, CD47 blockade also stimulates abscopal antitumor effects inhibiting the growth of non-irradiated SCLC tumors in mice receiving radiation. Similar abscopal antitumor effects were observed in colon cancer and lymphoma models. Surprisingly, these abscopal effects are completely independent of T cells but require macrophages that migrate into the non-irradiated tumor sites in response to inflammatory signals mediated by radiation and are locally activated by CD47 blockade to eliminate cancer cells. The systemic activation of antitumor macrophages following radiotherapy and CD47 blockade may be particularly important in cancer patients who suffer from metastatic disease.

2022-09-29 | GSE156106 | GEO

The abscopal effect of immune-radiation therapy in recurrent and metastatic cervical cancer: a narrative review.

Project description:Despite human papillomavirus vaccination and screening, in about 5% of cases, cervical cancer (CC) is discovered at an initial metastatic stage. Moreover, nearly one-third of patients with locally advanced CC (LACC) will have a recurrence of their disease during follow-up. At the stage of recurrent or metastatic CC, there are very few treatment options. They are considered incurable with a very poor prognosis. For many years, the standard of care was the combination of platinum-based drug and paclitaxel with the possible addition of bevacizumab. The most recent years have seen the development of the use of immune checkpoint inhibitors (ICIs) (pembrolizumab, cemiplimab and others) in patients with CC. They have shown long term responses with improved overall survival of patients in 1st line (in addition to chemotherapy) or 2nd line (as monotherapy) treatment. Another emerging drug is tisotumab vedotin, an antibody-drug conjugate targeting tissue factor. Radiation therapy (RT) often has a limited palliative indication in metastatic cancers. However, it has been observed that RT can induce tumor shrinkage both in distant metastatic tumors beyond the radiation field and in primary irradiated tumors. This is a rarely observed phenomenon, called abscopal effect, which is thought to be related to the immune system and allows a tumor response throughout the body. It would be the activation of the immune system induced by the irradiation of cancer cells that would lead to a specific type of apoptosis, the immunogenic cell death. Today, there is a growing consensus that combining RT with ICIs may boost abscopal response or cure rates for various cancers. Here we will review the potential abscopal effect of immune-radiation therapy in metastatic cervical cancer.

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Abscopal Effect Following Radiation Therapy in Cancer Patients: A New Look from the Immunological Point of View.

Project description:Abscopal effect, a radiobiology term meaning "away from target", was practically unheard of just ten years ago. This effect describes the elimination and cure of a non-treated tumor when another part of the body is irradiated. Successful treatment of cancer in patients with multiple metastatic foci has sporadically been reported. Abscopal effect after radiotherapy has been introduced as the key factor which induced an anticancer response in these metastatic lesions. Moreover, not receiving chemotherapy is reported to have a role in cancer regression after radiotherapy. Given this consideration, it can be hypothesized that standard radiotherapy doses, which usually classified as high-dose, may cause cancer cells to expose or release their sequestered antigens that had been previously masked. Furthermore, radiotherapy can decrease the suppressive effect of regulatory T cells which usually down modulate immune responses against cancers. Moreover, some data show that low dose total-body irradiation (TBI) alone (without standard localized high dose radiotherapy) may cause suppression of distant metastasis of tumor cells. Induction of a "whole body abscopal effect" can be involved in suppression of distant metastasis. Here we discuss whether cancer treatments could be more successful if immune system is boosted, not destroyed by the treatments such as chemotherapy.

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Macrophage contributes to radiation-induced anti-tumor abscopal effect on transplanted breast cancer by HMGB1/TNF-α signaling factors.

Project description:Objectives: The roles of innate immunity including macrophages in radiation-induced abscopal effect (RIAE) are ambiguous. In this study, we evaluated the role of macrophage in RIAE and the interaction of cytokines in tumor microenvironment after irradiation. Materials and Methods: Transplanted tumor of breast cancer cells in BalB/C mice, severe combined immunodeficiency (SCID) mice and non-obese diabetic (NOD)-SCID mice were irradiated with fractionation doses to observe anti-tumor abscopal effect. The underlying mechanism of RIAE was investigated by treating the mice with TNF-α inhibitor or macrophage depletion drug and analyzing the alteration of macrophage distribution in tumors. A co-culture system of breast cancer cells and macrophages was applied to disclose the signaling factors and related pathways involved in the RIAE. Results: The growth of nonirradiated tumor was effectively suppressed in mice with normal or infused macrophages but not in mice with insufficiency/depletion of macrophage or TNF-α inhibition, where M1-macrophage was mainly involved. Investigation of the bystander signaling factors in vitro demonstrated that HMGB1 released from irradiated breast cancer cells promoted bystander macrophages to secret TNF-α through TLR-4 pathway and further inhibited the proliferation and migration of non-irradiated cancer cells by PI3K-p110γ suppression. Conclusions: HMGB1 and TNF-α contributes to M1-macrophages facilitated systemic anti-tumor abscopal response triggered by radiotherapy in breast cancer, indicating that the combination of immunotherapy and radiotherapy may has important implication in enhancing the efficiency of tumor treatment.

| S-EPMC8040298 | biostudies-literature

Abscopal effect in pulmonary carcinoid tumor following ablative stereotactic body radiation therapy: a case report

Project description:Background The abscopal effect was described as early as the 1950s, when untreated tumors demonstrated a response after radiation therapy was delivered to an untreated, distant site. The mechanisms underlying this global response to otherwise localized therapy remain unknown, though there is increasing evidence that increased antigen expression following ablative radiotherapy may play a role. Case presentation We report a case of a 69-year-old African American woman with a history of metastatic typical pulmonary carcinoid with multiple lung nodules who had a significant decrease in size of an untreated left upper lobe nodule after stereotactic body radiation therapy to an oligoprogressive left lower lobe lesion. Conclusions To our knowledge, this report describes the first case of an abscopal effect in a typical pulmonary carcinoid. Further research is needed regarding the mechanisms responsible for this finding and the role of combining radiation therapy and cancer immunotherapy in patients with pulmonary carcinoid tumors.

| S-EPMC7532944 | biostudies-literature

Macrophage-mediated abscopal effects of radiation therapy

Project description:Macrophage-mediated abscopal effects of radiation therapy

| PRJNA656781 | ENA

Influence of intestinal microbial metabolites on the abscopal effect after radiation therapy combined with immune checkpoint inhibitors.

Project description:BackgroundMost clinical studies failed to elicit a strong antitumor immune response and subsequent systemic tumor regression after radiation therapy (RT), even in combination with the immune checkpoint inhibitors (ICI) anti-CTLA4 or anti-PD1. Mechanistically, type I interferon (IFN-I) activation is essential for the development of such abscopal effects (AE); however, mechanisms driving or limiting IFN-I activation are ill defined. Groundbreaking discoveries have shown that antibiotics (ABx) can affect oncological outcomes and that microbiota-derived metabolites can modulate systemic antitumor immunity. Recent studies have demonstrated that the bacterial metabolites desaminotyrosine (DAT) and indole-3-carboxaldehyde (ICA) can enhance IFN-I activation in models of inflammatory diseases.Materials and methodsThe subcutaneous bilateral MC38 tumor model is a widely used experimental tool to study the AE in mice. We applied it to explore the influence of broad-spectrum ABx, DAT and ICA on the AE after radioimmunotherapy (RIT). We performed 1x8 Gy of the primary tumor ± anti-CTLA4 or anti-PD1, and ± daily oral application of ABx or metabolites.ResultCombinatory ABx had neither a significant effect on tumor growth of the irradiated tumor nor on tumor progression of the abscopal tumor after RIT with anti-CTLA4. Furthermore, DAT and ICA did not significantly impact on the AE after RIT with anti-CTLA4 or anti-PD1. Surprisingly, ICA even appears to reduce outcomes after RIT with anti-CTLA4.ConclusionWe did not find a significant impact of combinatory ABx on the AE. Experimental application of the IFN-I-inducing metabolites DAT or ICA did not boost the AE after combined RIT. Additional studies are important to further investigate whether the intestinal microbiota or specific microbiota-derived metabolites modulate the AE.

| S-EPMC10945164 | biostudies-literature

Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer.

Project description:Purpose: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model.Methods: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3 × 8 Gy)±local HT, mild (HTM, 43 °C/20 min) or partially ablative (HTAbl, 45 °C/5 min plus 43 °C/15 min),±IT with anti-PD-1 and anti-CTLA-4 antibodies (both 4 × 10 mg/kg, i.p.). Tumor growth was measured daily. Two weeks after treatment, lungs and livers were harvested for histopathology evaluation of metastases.Results: Compared to untreated controls, all treatment groups demonstrated a decreased tumor volume; however, when compared against surgical resection, only RT + HTM+IT, RT + HTAbl+IT and RT + HTAbl had similar or smaller tumors. These cohorts showed more infiltration of CD3+ T-lymphocytes into the primary tumor. Tumor growth effects were partially reversed with T-cell depletion. Combinations that proved most effective for primary tumors generated modest reductions in numbers of lung metastases. Conversely, numbers of lung metastases showed potential to increase following HT + IT treatment, particularly when compared to RT. Compared to untreated controls, there was no improvement in survival with any treatment.Conclusions: Single-fraction MION HT added to RT + IT improved local tumor control and recruitment of CD3+ T-lymphocytes, with only a modest effect to reduce lung metastases and no improvement in overall survival. HT + IT showed potential to increase metastatic dissemination to lungs.

| S-EPMC7017719 | biostudies-literature

CD169-positive macrophages enhance abscopal effect of radiofrequency ablation therapy in liver cancer.

Project description:Radiofrequency ablation (RFA) is a widely used and effective treatment for primary or metastatic liver cancer with small-size lesions. However, the therapeutic effectiveness of RFA in controlling metastatic lesion or recurrence is still limited. As the major cell population in tumor microenvironment (TME), macrophages have been reported to be recruited to RFA-treated lesion, but their roles are still unclear. Herein, we successfully established the mouse model mimicking RFA-induced abscopal effect, in which RFA eliminated the local orthotopic liver tumor but failed to control growth of distant tumor. Correspondently, RFA suppressed protumoral activation of local tumor-associated macrophages (TAMs), but failed to reprogram TAMs in distance. Importantly, although RFA led to reduced proportion of hepatic CD169+ macrophages in local and decreased expression of immune inhibitory molecules Tim-3 and PD-L1, these alterations were not observed for CD169+ macrophages in distant TME. Further RNA-seq and flow cytometry analysis showed that hepatic CD169+ macrophages contributed to reprograming TME through recruiting CD8+ T/NK cells and suppressing accumulation of MDSCs/Tregs. Consistently, depletion of CD169+ macrophages in CD169-DTR mouse greatly promoted liver tumor progression and largely dampened RFA-induced tumor suppression. Notably, transfer of CD169+ macrophages synergistically enhanced RFA-induced inhibition of distant tumor. To our knowledge, this is the first study which demonstrates hepatic CD169+ macrophages as a key factor responsible for RFA-induced abscopal effect. Our data suggest RFA with transfer of CD169+ macrophages as a promising combination therapy to lessen metastasis or recurrence of liver cancer in patients.

| S-EPMC8662336 | biostudies-literature

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