[ 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 ]
- JOURNAL OF TRANSLATIONAL MEDICINE
[ 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, R
Martorelli, D
[ 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-gamma ELISPOT and
IFN-gamma/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 CD8(+) T 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.
[ URL ]
- http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS&DestLinkType=FullRecord;UT=WOS:000357220500001