Online citations, reference lists, and bibliographies.
← Back to Search

Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects Of Potential Therapeutic Relevance In Oligometastatic Breast Cancer

E. Muraro, C. Furlan, M. Avanzo, D. Martorelli, E. Comaro, A. Rizzo, D. A. Faè, M. Berretta, L. Militello, A. Del Conte, S. Spazzapan, R. Dolcetti, M. Trovò
Published 2017 · Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
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.
This paper references
10.1186/s40425-016-0133-1
Can abscopal effects of local radiotherapy be predicted by modeling T cell trafficking?
S. Demaria (2016)
10.1186/bcr3620
Immune approaches to the treatment of breast cancer, around the corner?
C. Criscitiello (2014)
10.1080/08820139.2016.1197242
Regulatory T Cells and Cancer: A Two-Sided Story
K. Wang (2016)
10.1016/j.radonc.2017.08.032
Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial.
M. Trovò (2018)
10.1016/j.radonc.2015.11.016
Comparative analysis of the effects of radiotherapy versus radiotherapy after adjuvant chemotherapy on the composition of lymphocyte subpopulations in breast cancer patients.
E. Sage (2016)
10.1158/1078-0432.CCR-11-0544
TGFβ1 Inhibition Increases the Radiosensitivity of Breast Cancer Cells In Vitro and Promotes Tumor Control by Radiation In Vivo
Fanny Bouquet (2011)
10.1146/ANNUREV.ME.39.020188.000431
Tumors of the immunocompromised patient.
I. Penn (1988)
10.1111/J.1399-0039.2005.00345.X
New strategies for efficient typing of HLA class-II loci DQB1 and DRB1 by using Pyrosequencing.
P. Entz (2005)
10.2174/156800907780006896
Indoleamine 2,3-dioxygenase in immune suppression and cancer.
A. J. Muller (2007)
10.1177/1060028016642786
Immunotherapy
Salma Afifi (2016)
10.1007/s10549-011-1855-x
Role of interleukin-10 in breast cancer
Hamidullah (2011)
a two-sided story
K Wang (2016)
10.1056/NEJMoa1112824
Immunologic correlates of the abscopal effect in a patient with melanoma.
M. Postow (2012)
10.1182/BLOOD.V110.11.644.644
Results of a Prospective Phase II Trial of Limited and Extended Rituximab Treatment in Nodular Lymphocyte Predominant Hodgkin’s Disease (NLPHD).
S. Horning (2007)
10.1007/s00262-008-0530-5
Systemic immune effects of adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide and/or radiotherapy in breast cancer: a longitudinal study
F. Mozaffari (2008)
gamma-radiation promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo
A Sharma (2011)
10.1016/j.canlet.2013.09.018
Abscopal effects of radiation therapy: a clinical review for the radiobiologist.
S. Siva (2015)
10.3389/fimmu.2014.00102
Radiation for Awakening the Dormant Immune System, a Promising Challenge to be Explored
L. de la Cruz-Merino (2014)
10.3389/fimmu.2017.00229
Barriers to Radiation-Induced In Situ Tumor Vaccination
E. Wennerberg (2017)
10.1016/j.acthis.2011.10.007
An immunohistochemical study of interleukin-8 (IL-8) in breast cancer.
D. A. P. Zuccari (2012)
implications for vaccine design
RA Seder (2008)
10.1186/1471-2407-14-954
Anthracycline-free neoadjuvant therapy induces pathological complete responses by exploiting immune proficiency in HER2+ breast cancer patients
G. Miolo (2014)
10.1038/nri2274
T-cell quality in memory and protection: implications for vaccine design
R. Seder (2008)
10.1016/j.ijrobp.2009.06.017
Stereotactic body radiation therapy for early-stage non-small-cell lung cancer: the pattern of failure is distant.
J. Bradley (2010)
10.1158/1078-0432.CCR-16-2946
A Pilot Study of Stereotactic Body Radiation Therapy Combined with Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma
A. Singh (2017)
10.1038/nature14292
Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer
Christina Twyman-Saint Victor (2015)
10.1016/j.semradonc.2014.07.004
Combination of radiotherapy and immune checkpoint inhibitors.
Karsten A. Pilones (2015)
10.1158/1538-7445.AM2014-632
Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing
S. Gameiro (2014)
10.1007/s10549-006-9328-3
Significance of interleukin-6 (IL-6) in breast cancer (review)
H. Knüpfer (2006)
10.1186/s12967-015-0567-0
Improved Natural Killer cell activity and retained anti-tumor CD8+ T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy
E. Muraro (2015)
10.1093/annonc/mdu235
The immunogenicity of breast cancer--molecular subtypes matter.
C. Denkert (2014)
10.1155/2013/281958
The Impact of the Myeloid Response to Radiation Therapy
M. Gough (2013)
10.1126/SCIENCE.285.5428.727
Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.
S. Bauer (1999)
10.1097/CJI.0000000000000141
Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic Solid Tumors
J. Ribeiro Gomes (2016)
10.1016/j.breast.2015.12.002
Stereotactic body radiation therapy: A promising chance for oligometastatic breast cancer.
M. Scorsetti (2016)
a safe and effective combination
A Aboudaram (2017)
10.3389/FIMMU.2014.00102
Radiation for Awakening the Dormant Immune System, a Promising Challenge to be Explored.
L. Cruz-Merino (2014)
lessons from our 30-year experience with oligometastatic breast cancer patients and literature review
H Kobayashi (2012)
10.1158/1078-0432.CCR-09-0265
Fractionated but Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect when Combined with Anti–CTLA-4 Antibody
M. Z. Dewan (2009)
10.1158/0008-5472.CAN-05-3918
Gene expression profiling revealed survivin as a target of 3,3'-diindolylmethane-induced cell growth inhibition and apoptosis in breast cancer cells.
K. Rahman (2006)
a disease-oriented approach
U Ricardi (2016)
10.1034/J.1399-0039.1999.530208.X
Molecular typing for HLA class I using ARMS-PCR: further developments following the 12th International Histocompatibility Workshop.
S. Tonks (1999)
10.1007/978-1-4020-5614-7_2008
Longitudinal Study
M. O'Connor (2013)
10.1371/journal.pone.0028217
γ-Radiation Promotes Immunological Recognition of Cancer Cells through Increased Expression of Cancer-Testis Antigens In Vitro and In Vivo
A. Sharma (2011)
10.3389/fimmu.2016.00591
The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung
F. Wirsdörfer (2016)
10.3389/fimmu.2016.00610
Chemoradiation Increases PD-L1 Expression in Certain Melanoma and Glioblastoma Cells
A. Derer (2016)
10.1093/jnci/djs629
Combining radiotherapy and cancer immunotherapy: a paradigm shift.
S. Formenti (2013)
10.1016/S0022-5347(05)67278-3
Serum immunosuppressive acidic protein and natural killer cell activity in patients with metastatic renal cell carcinoma before and after nephrectomy.
K. Fujikawa (2000)
10.1158/1078-0432.CCR-15-1315
New Strategies in Breast Cancer: Immunotherapy
L. Pusztai (2016)
10.1159/000358750
Oligometastatic Breast Cancer: A Shift from Palliative to Potentially Curative Treatment?
S. Di Lascio (2014)
10.1667/RR3031.1
Cytokines in Radiobiological Responses: A Review
D. Schaue (2012)
10.1097/jnn.0b013e318274cc4d
A Review of the
Robert Wolpert (1985)
10.1158/2326-6066.CIR-13-0079
Alternative Variants of Human HYDIN Are Novel Cancer-Associated Antigens Recognized by Adaptive Immunity
Karoline Laske (2013)
10.1016/j.bbcan.2014.04.009
Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells.
Daniel Heylmann (2014)
10.1158/0008-5472.CAN-15-1423
Abscopal Benefits of Localized Radiotherapy Depend on Activated T-cell Trafficking and Distribution between Metastatic Lesions.
J. Poleszczuk (2016)
10.1080/2162402X.2015.1046028
A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab
R. A. Chandra (2015)
10.1186/1479-5876-6-25
Correlation between NK function and response to trastuzumab in metastatic breast cancer patients
A. Beano (2008)
10.1093/jrr/rrw006
Clinical applications of stereotactic radiation therapy for oligometastatic cancer patients: a disease-oriented approach
U. Ricardi (2016)
10.1007/s00262-004-0617-6
Paclitaxel probably enhances cytotoxicity of natural killer cells against breast carcinoma cells by increasing perforin production
Makoto Kubo (2004)
10.1016/J.CTRV.2005.03.004
The controversial abscopal effect.
J. Kaminski (2005)
10.1007/BF00131170
Paradigm shift
F. Golley (2004)
10.1158/0008-5472.CAN-14-3511
TGFβ Is a Master Regulator of Radiation Therapy-Induced Antitumor Immunity.
Claire Vanpouille-Box (2015)
10.1093/annonc/mdv395
Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial.
G. Bianchini (2015)
10.1016/j.semradonc.2013.05.009
Radiation as an immune modulator.
B. Burnette (2013)
10.18632/ONCOTARGET.1637
Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR
Ulrike M. Litzenburger (2014)
10.1200/JCO.2009.22.8775
Identification of subtypes in human epidermal growth factor receptor 2--positive breast cancer reveals a gene signature prognostic of outcome.
J. Staaf (2010)
10.1097/CMR.0000000000000386
Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination
A. Aboudaram (2017)
10.1007/s12282-012-0347-0
Possible clinical cure of metastatic breast cancer: lessons from our 30-year experience with oligometastatic breast cancer patients and literature review
T. Kobayashi (2012)
10.1155/2011/439752
The Confluence of Stereotactic Ablative Radiotherapy and Tumor Immunology
S. Finkelstein (2011)



This paper is referenced by
10.3390/ijms20020382
Cytokine Modulation in Breast Cancer Patients Undergoing Radiotherapy: A Revision of the Most Recent Studies
Raffaella Marconi (2019)
10.3389/fonc.2020.00004
Hypofractionated Irradiation Suppressed the Off-Target Mouse Hepatocarcinoma Growth by Inhibiting Myeloid-Derived Suppressor Cell-Mediated Immune Suppression
Junying Chen (2020)
10.21037/apm.2020.03.31
Oligometastases: history of a hypothesis.
M. Milano (2020)
10.3390/cancers11050689
Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation
R. Berzaghi (2019)
10.1016/j.radonc.2019.06.001
A translational concept of immuno-radiobiology.
Bodo E. Lippitz (2019)
10.1080/0284186X.2018.1554259
Rationale for combination of radiation therapy and immune checkpoint blockers to improve cancer treatment
O. Dahl (2019)
10.1016/j.immuni.2018.03.007
Combination Cancer Therapy with Immune Checkpoint Blockade: Mechanisms and Strategies.
Shetal A Patel (2018)
10.1080/14737140.2019.1537785
Targeted and immuno-biology driven treatment strategies for triple-negative breast cancer: current knowledge and future perspectives
C. Fremd (2018)
10.1186/s40425-019-0634-9
Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination
M. Grapin (2019)
10.1016/j.ijrobp.2018.04.038
Stereotactic Ablative Radiation Therapy Induces Systemic Differences in Peripheral Blood Immunophenotype Dependent on Irradiated Site.
H. McGee (2018)
10.3389/fimmu.2019.01337
Recent Findings in the Regulation of Programmed Death Ligand 1 Expression
Xiangfeng Shen (2019)
10.1097/SLA.0000000000003649
Neoadjuvant Radiotherapy Versus Surgery Alone for Stage II/III Mid-low Rectal Cancer With or Without High-risk Factors
Xiang-bing Deng (2019)
10.1016/J.RADONC.2018.11.022
Oligometastatic breast cancer treated with hypofractionated stereotactic radiotherapy: Some patients survive longer than a decade.
M. Milano (2019)
10.1634/theoncologist.2019-IO-S1-s04
The Role of Radiation Oncology in Immuno‐Oncology
Xiang-jiao Meng (2019)
10.1002/acm2.12728
Three discipline collaborative radiation therapy (3DCRT) special debate: The single most important factor in determining the future of SBRT is immune response
C. Grassberger (2019)
10.3389/fonc.2019.01551
Post-mastectomy Radiotherapy in T1-2 Breast Cancer Patients With One to Three Lymph Node Metastases: A Propensity Score Matching Analysis
Maoshan Chen (2019)
10.1016/j.breast.2018.12.014
Combination of peripheral neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio is predictive of pathological complete response after neoadjuvant chemotherapy in breast cancer patients.
V. Graziano (2019)
10.3389/fonc.2020.00874
Immunomodulation of NK Cells by Ionizing Radiation
Jiarui Chen (2020)
10.1111/bcp.14351
Radiation therapy and the innate immune response: Clinical implications for immunotherapy approaches
V. Gómez (2020)
10.2174/1389200221666200303124946
Decoding novel mechanisms and emerging therapeutic strategies in breast cancer resistance.
Sadat Shafi (2020)
10.1016/j.biopha.2019.108800
Chemoresistance mechanisms of breast cancer and their countermeasures.
Xiwei Ji (2019)
10.1007/978-3-319-52619-5_106-1
Immune Modulatory Effects of Radiotherapy
B. Frey (2019)
10.1016/j.semcancer.2019.08.026
Tumor Biology and Multidisciplinary Strategies of Oligometastasis in Gastrointestinal Cancers.
Yue Zhao (2019)
10.3389/fonc.2020.00987
Extracranial Stereotactic Body Radiotherapy in Oligometastatic or Oligoprogressive Breast Cancer
F. Weykamp (2020)
10.3390/cancers11070911
Decoding Immune Heterogeneity of Triple Negative Breast Cancer and Its Association with Systemic Inflammation
S. Romero-Cordoba (2019)
10.1080/14737140.2019.1686980
Stereotactic body radiotherapy in patients with multiple lung tumors: a focus on lung dosimetric constraints
M. Milano (2019)
10.3390/cancers13030508
Radical Hemithoracic Radiotherapy Induces Systemic Metabolomics Changes That Are Associated with the Clinical Outcome of Malignant Pleural Mesothelioma Patients
Emanuela Di Gregorio (2021)
Semantic Scholar Logo Some data provided by SemanticScholar