Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer
Local irradiation of cancer through radiotherapy can induce spontaneous regression of non-directly irradiated lesions, suggesting the involvement of systemic antitumor immune responses. In oligometastatic breast cancer (BC) patients, the use of stereotactic body radiotherapy (SBRT) favors the local...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2017-11-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01476/full |
| _version_ | 1828778102963044352 |
|---|---|
| author | Elena Muraro Carlo Furlan Michele Avanzo Debora Martorelli Elisa Comaro Aurora Rizzo Damiana A. Fae’ Massimiliano Berretta Loredana Militello Alessandro Del Conte Simon Spazzapan Riccardo Dolcetti Riccardo Dolcetti Marco Trovo’ |
| author_facet | Elena Muraro Carlo Furlan Michele Avanzo Debora Martorelli Elisa Comaro Aurora Rizzo Damiana A. Fae’ Massimiliano Berretta Loredana Militello Alessandro Del Conte Simon Spazzapan Riccardo Dolcetti Riccardo Dolcetti Marco Trovo’ |
| author_sort | Elena Muraro |
| collection | DOAJ |
| description | Local irradiation of cancer through radiotherapy can induce spontaneous regression of non-directly irradiated lesions, suggesting the involvement of systemic antitumor immune responses. In oligometastatic breast cancer (BC) patients, the use of stereotactic body radiotherapy (SBRT) favors the local control of treated lesions and may contribute to break local tolerance and release tumor-associated antigens (TAAs), improving host antitumor immunity. We performed a detailed immunomonitoring of BC patients undergoing SBRT to verify its ability to “switch on” the anti-tumor immunity both systemically, in peripheral blood, and locally, employing in vitro BC models. Twenty-one BC patients with ≤6 metastases were treated with 3 daily doses of 10 Gy with SBRT. Blood samples for immune profiling were collected before and after treatment. One month after treatment a third of patients displayed the boosting or even the de novo appearance of polyfunctional CD4+ and CD8+ T cell responses against known BC TAAs (survivin, mammaglobin-A, HER2), through intracellular staining in flow cytometry. Half of patients showed increased numbers of activated natural killer (NK) cells, measured with multispectral flow cytometry, immediately after the first dose of SBRT. Interestingly, high levels of activated NK cells at diagnosis correlated with a longer progression-free survival. BC in vitro models, treated with the same SBRT modality, showed enhanced expression of MHC class-I and class-II, major histocompatibility complex class I-related chain A/B, and Fas molecules, and increased release of pro-inflammatory cytokines, such as IL-1β and TNF-α. Consistently, we noticed enhanced production of perforin by CD4+ T cells when patients’ lymphocytes were cultured in the presence of irradiated BC cell line, compared to untreated targets. Besides immunogenic effects, SBRT also enhanced the percentages of circulating regulatory T cells, and increased indoleamine 2,3 dioxygenase and PD-L1 expression in BC in vitro models. These results suggest that SBRT may boost host antitumor immune responses also in an advanced disease setting such as oligometastatic BC, by inducing immunomodulating effects both locally and systemically. However, the concomitant induction of immunosuppressive pathways suggests that a combination with immunotherapy could further enhance the in situ vaccination ability of radiotherapy, possibly further improving the curative potential of SBRT in this subset of patients. |
| first_indexed | 2024-12-11T16:34:33Z |
| format | Article |
| id | doaj.art-f00bf33f949342d2af6c4b7ab9ba19d6 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T16:34:33Z |
| publishDate | 2017-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f00bf33f949342d2af6c4b7ab9ba19d62022-12-22T00:58:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-11-01810.3389/fimmu.2017.01476294725Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast CancerElena Muraro0Carlo Furlan1Michele Avanzo2Debora Martorelli3Elisa Comaro4Aurora Rizzo5Damiana A. Fae’6Massimiliano Berretta7Loredana Militello8Alessandro Del Conte9Simon Spazzapan10Riccardo Dolcetti11Riccardo Dolcetti12Marco Trovo’13Immunopathology and Biomarker Unit, Department of Translational Research, CRO Aviano National Cancer Institute, Aviano, ItalyDepartment of Radiation Oncology, CRO Aviano National Cancer Institute, Aviano, ItalyDivision of Medical Physics, CRO Aviano National Cancer Institute, Aviano, ItalyImmunopathology and Biomarker Unit, Department of Translational Research, CRO Aviano National Cancer Institute, Aviano, ItalyImmunopathology and Biomarker Unit, Department of Translational Research, CRO Aviano National Cancer Institute, Aviano, ItalyImmunopathology and Biomarker Unit, Department of Translational Research, CRO Aviano National Cancer Institute, Aviano, ItalyImmunopathology and Biomarker Unit, Department of Translational Research, CRO Aviano National Cancer Institute, Aviano, ItalyDepartment of Medical Oncology, CRO Aviano National Cancer Institute, Aviano, ItalyDepartment of Medical Oncology, CRO Aviano National Cancer Institute, Aviano, ItalyDepartment of Medical Oncology, Pordenone General Hospital, Aviano, ItalyDepartment of Medical Oncology, CRO Aviano National Cancer Institute, Aviano, ItalyImmunopathology and Biomarker Unit, Department of Translational Research, CRO Aviano National Cancer Institute, Aviano, ItalyTranslational Research Institute, University of Queensland Diamantina Institute, Brisbane, QLD, AustraliaDepartment of Radiation Oncology, Azienda Sanitaria Universitaria Integrata of Udine, Udine, ItalyLocal irradiation of cancer through radiotherapy can induce spontaneous regression of non-directly irradiated lesions, suggesting the involvement of systemic antitumor immune responses. In oligometastatic breast cancer (BC) patients, the use of stereotactic body radiotherapy (SBRT) favors the local control of treated lesions and may contribute to break local tolerance and release tumor-associated antigens (TAAs), improving host antitumor immunity. We performed a detailed immunomonitoring of BC patients undergoing SBRT to verify its ability to “switch on” the anti-tumor immunity both systemically, in peripheral blood, and locally, employing in vitro BC models. Twenty-one BC patients with ≤6 metastases were treated with 3 daily doses of 10 Gy with SBRT. Blood samples for immune profiling were collected before and after treatment. One month after treatment a third of patients displayed the boosting or even the de novo appearance of polyfunctional CD4+ and CD8+ T cell responses against known BC TAAs (survivin, mammaglobin-A, HER2), through intracellular staining in flow cytometry. Half of patients showed increased numbers of activated natural killer (NK) cells, measured with multispectral flow cytometry, immediately after the first dose of SBRT. Interestingly, high levels of activated NK cells at diagnosis correlated with a longer progression-free survival. BC in vitro models, treated with the same SBRT modality, showed enhanced expression of MHC class-I and class-II, major histocompatibility complex class I-related chain A/B, and Fas molecules, and increased release of pro-inflammatory cytokines, such as IL-1β and TNF-α. Consistently, we noticed enhanced production of perforin by CD4+ T cells when patients’ lymphocytes were cultured in the presence of irradiated BC cell line, compared to untreated targets. Besides immunogenic effects, SBRT also enhanced the percentages of circulating regulatory T cells, and increased indoleamine 2,3 dioxygenase and PD-L1 expression in BC in vitro models. These results suggest that SBRT may boost host antitumor immune responses also in an advanced disease setting such as oligometastatic BC, by inducing immunomodulating effects both locally and systemically. However, the concomitant induction of immunosuppressive pathways suggests that a combination with immunotherapy could further enhance the in situ vaccination ability of radiotherapy, possibly further improving the curative potential of SBRT in this subset of patients.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01476/fulloligometastatic breast cancerstereotactic body radiotherapyantitumor T cell responsesimmunomodulationradiotherapy immunogenicity |
| spellingShingle | Elena Muraro Carlo Furlan Michele Avanzo Debora Martorelli Elisa Comaro Aurora Rizzo Damiana A. Fae’ Massimiliano Berretta Loredana Militello Alessandro Del Conte Simon Spazzapan Riccardo Dolcetti Riccardo Dolcetti Marco Trovo’ Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer Frontiers in Immunology oligometastatic breast cancer stereotactic body radiotherapy antitumor T cell responses immunomodulation radiotherapy immunogenicity |
| title | Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer |
| title_full | Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer |
| title_fullStr | Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer |
| title_full_unstemmed | Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer |
| title_short | Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer |
| title_sort | local high dose radiotherapy induces systemic immunomodulating effects of potential therapeutic relevance in oligometastatic breast cancer |
| topic | oligometastatic breast cancer stereotactic body radiotherapy antitumor T cell responses immunomodulation radiotherapy immunogenicity |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01476/full |
| work_keys_str_mv | AT elenamuraro localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT carlofurlan localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT micheleavanzo localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT deboramartorelli localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT elisacomaro localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT aurorarizzo localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT damianaafae localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT massimilianoberretta localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT loredanamilitello localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT alessandrodelconte localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT simonspazzapan localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT riccardodolcetti localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT riccardodolcetti localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer AT marcotrovo localhighdoseradiotherapyinducessystemicimmunomodulatingeffectsofpotentialtherapeuticrelevanceinoligometastaticbreastcancer |