Improved Natural Killer cell activity and retained anti-tumor CD8<sup>+</sup> T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy

Muraro, E., Comaro, E., Talamini, R., Turchet, E., Miolo, G., Scalone, S., Militello, L., Lombardi, D., Spazzapan, S., Perin, T., Massarut, S., Crivellari, D., Dolcetti, Riccardo and Martorelli, D. (2015) Improved Natural Killer cell activity and retained anti-tumor CD8<sup>+</sup> T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy. Journal of Translational Medicine, 13 204: . doi:10.1186/s12967-015-0567-0


Author Muraro, E.
Comaro, E.
Talamini, R.
Turchet, E.
Miolo, G.
Scalone, S.
Militello, L.
Lombardi, D.
Spazzapan, S.
Perin, T.
Massarut, S.
Crivellari, D.
Dolcetti, Riccardo
Martorelli, D.
Title 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
Journal name Journal of Translational Medicine   Check publisher's open access policy
ISSN 1479-5876
Publication date 2015-06-27
Sub-type Article (original research)
DOI 10.1186/s12967-015-0567-0
Open Access Status DOI
Volume 13
Issue 204
Total pages 134
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Formatted abstract
Background: Locally advanced HER2-overexpressing breast cancer (BC) patients achieve a high rate of pathological complete responses (pCR) after neoadjuvant chemotherapy (NC). The apparently unaltered immune proficiency of these patients together with the immune-modulating activities of NC drugs suggest a potential contribution of host immunity in mediating clinical responses. We thus performed an extensive immunomonitoring in locally advanced BC patients undergoing NC to identify immunological correlates of pCR induction.

Methods: The immune profile of 40 HER2-positive and 38 HER2-negative BC patients was characterized at diagnosis and throughout NC (Paclitaxel and Trastuzumab, or Docetaxel and Epirubicin, respectively). The percentages of circulating immune cell subsets including T and B lymphocytes, Natural Killer (NK) cells, regulatory T cells, T helper 17 lymphocytes, were quantified by multiparametric flow cytometry. NK cells functional activity was evaluated through the analysis of NF-kB nuclear translocation by Multispectral flow cytometry, and with the in vitro monitoring of Trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC). CD8+ T cell responses against six different tumor-associated antigens (TAA) were characterized by IFN-γ ELISPOT and IFN-γ/IL-2 DualSpot assays.

Results: After NC, HER2-positive patients showed a significant increase in the number of NK cells and regulatory T cells irrespective of the pathological response, whereas patients undergoing a pCR disclosed higher percentages of T helper 17 cells. Notably, a significant increase in the number of activated NK cells was observed only in HER2-positive patients achieving a pCR. Characterization of anti-tumor T cell responses highlighted sustained levels of CD8T cells specific for survivin and mammaglobin-A throughout NC in patients undergoing a pCR in both arms. Moreover, HER2-positive patients achieving a pCR were characterized by a multi-epitopic and polyfunctional anti-tumor T cell response, markedly reduced in case of partial response.

Conclusions: These results indicate that maintenance of functional T cell responses against selected antigens and improvement of NK cell proficiency during NC are probably critical requirements for pCR induction, especially in HER2-positive BC patients.
Keyword Antitumor immunity
Breast cancer
CD8+ T lymphocytes
HER2-overexpression
Immunomonitoring
Neoadjuvant chemotherapy
NK cells
Pathological complete response
Polyfunctional T cell responses
Th17 cells
Q-Index Code CX
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
UQ Diamantina Institute Publications
 
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