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J Transl Med. 2015 Jun 27;13:204. doi: 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.

Author information

1
Cancer Bio-Immunotherapy Unit, Department of Translational Research, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. emuraro@cro.it.
2
Cancer Bio-Immunotherapy Unit, Department of Translational Research, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. ecomaro@cro.it.
3
Unit of Epidemiology and Biostatistics, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. talaminir@gmail.com.
4
Scientific Direction, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. eturchet@cro.it.
5
Department of Medical Oncology, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. gmiolo@cro.it.
6
Department of Medical Oncology, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. sscalone@cro.it.
7
Department of Medical Oncology, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. lomilitello@gmail.com.
8
Department of Medical Oncology, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. dlombardi@cro.it.
9
Department of Medical Oncology, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. sspazzapan@cro.it.
10
Department of Pathology, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. tperin@cro.it.
11
Division of Breast Surgical Oncology, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. smassarut@cro.it.
12
Department of Medical Oncology, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. dianacrivellari@gmail.com.
13
Cancer Bio-Immunotherapy Unit, Department of Translational Research, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. rdolcetti@cro.it.
14
Cancer Bio-Immunotherapy Unit, Department of Translational Research, CRO Aviano, IRCCS, National Cancer Institute, Via F. Gallini 2, 33081, Aviano, PN, Italy. dmartorelli@cro.it.

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 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. Trail registration:

TRIAL REGISTRATION NUMBER:

NCT02307227, registered on ClinicalTrials.gov ( http://www.clinicaltrials.gov , November 26, 2014).

PMID:
26116238
PMCID:
PMC4483222
DOI:
10.1186/s12967-015-0567-0
[Indexed for MEDLINE]
Free PMC Article

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