Local high-dose radiotherapy induces systemic immunomodulating effects of potential therapeutic relevance in oligometastatic breast cancer

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, Marco Trovo'

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article number1476
Number of pages19
JournalFrontiers in Immunology
Volume8
DOIs
Publication statusPublished - Nov 6 2017

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Therapeutic Uses
Radiosurgery
Radiotherapy
Breast Neoplasms
Neoplasm Antigens
Natural Killer Cells
Mammaglobin A
Immunity
Flow Cytometry
Indoleamine-Pyrrole 2,3,-Dioxygenase
T-Lymphocytes
Perforin
Regulatory T-Lymphocytes
Immunosuppressive Agents
Major Histocompatibility Complex
Interleukin-1
Immunotherapy
Disease-Free Survival
Neoplasms
Vaccination

Keywords

  • Antitumor T cell responses
  • Immunomodulation
  • Oligometastatic breast cancer
  • Radiotherapy immunogenicity
  • Stereotactic body radiotherapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Local high-dose radiotherapy induces systemic immunomodulating effects of potential therapeutic relevance in oligometastatic breast cancer. / Muraro, Elena; Furlan, Carlo; Avanzo, Michele; Martorelli, Debora; Comaro, Elisa; Rizzo, Aurora; Fae', Damiana A.; Berretta, Massimiliano; Militello, Loredana; Del Conte, Alessandro; Spazzapan, Simon; Dolcetti, Riccardo; Trovo', Marco.

In: Frontiers in Immunology, Vol. 8, 1476, 06.11.2017.

Research output: Contribution to journalArticle

Muraro, Elena ; Furlan, Carlo ; Avanzo, Michele ; Martorelli, Debora ; Comaro, Elisa ; Rizzo, Aurora ; Fae', Damiana A. ; Berretta, Massimiliano ; Militello, Loredana ; Del Conte, Alessandro ; Spazzapan, Simon ; Dolcetti, Riccardo ; Trovo', Marco. / Local high-dose radiotherapy induces systemic immunomodulating effects of potential therapeutic relevance in oligometastatic breast cancer. In: Frontiers in Immunology. 2017 ; Vol. 8.
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AU - Rizzo, Aurora

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AU - Berretta, Massimiliano

AU - Militello, Loredana

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