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T cells sensitized with breast tumor progenitor cell vaccine have therapeutic activity against spontaneous HER2/neu tumors

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Abstract

Cancer progenitor cells are critical for tumor initiation and recurrence so they are an important therapeutic target. We tested whether T cells could recognize tumor antigens expressed by breast cancer progenitor cells and acquire therapeutic activity against established metastases or delay onset of spontaneous tumors. Breast tumors were derived from HER2/neu transgenic mice and propagated in vitro under conditions that selected progenitor cells which were then used as an irradiated whole cell vaccine. A minor subset of recently sensitized T cells was isolated from vaccine-draining lymph nodes then activated in vitro to achieve numerical expansion. We show that the tumor progenitor cell vaccines reversed tolerance to a known HER2/neu epitope, otherwise inhibited by Treg cells. Additional shared tumor antigens were recognized because a Neuneg subclone also induced a Th1 type immune response against breast tumors. Adoptive transfer of in vitro activated lymph node T cells-mediated regression of established metastases from multiple independently derived breast tumor lines. Moreover, adoptive transfer of effector T cells into Neu-tolerant mice, months before the onset of spontaneous tumors, significantly postponed tumor development. Interestingly, T-cell-mediated lysis of metastases stimulated an IgG response to HER2/neu as well as other shared antigens. In summary, tumor progenitor cells contain shared antigens which can lead to a cross-protective T-cell response. Moreover, antigens acquired during immune-mediated tumor destruction are presented in a manner conducive to reversal of tolerance and Ig class switching. These complementary effector mechanisms might augment therapy by eliminating refractory breast cancer stem cells.

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Acknowledgments

Research support from Susan G. Komen, KG081511 (to L. X. W), NIH RO1CA151496 (to L. X. W), and NIH RO1CA120893 (to G. E. P).

Conflict of interest

The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Immunology, Cleveland Clinic, NE62, 9500 Euclid Ave, Cleveland, OH, 44195, USA

    Li-Xin Wang & Gregory E. Plautz

  2. Pediatrics, Cleveland Clinic, Cleveland, OH, 44195, USA

    Gregory E. Plautz

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  1. Li-Xin Wang
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Correspondence to Li-Xin Wang.

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Wang, LX., Plautz, G.E. T cells sensitized with breast tumor progenitor cell vaccine have therapeutic activity against spontaneous HER2/neu tumors. Breast Cancer Res Treat 134, 61–70 (2012). https://doi.org/10.1007/s10549-011-1912-5

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  • DOI: https://doi.org/10.1007/s10549-011-1912-5

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