TY - JOUR
T1 - Trastuzumab increases HER2 uptake and cross-presentation by dendritic cells
AU - Gall, Victor A.
AU - Philips, Anne V.
AU - Qiao, Na
AU - Clise-Dwyer, Karen
AU - Perakis, Alexander A.
AU - Zhang, Mao
AU - Clifton, Guy T.
AU - Sukhumalchandra, Pariya
AU - Ma, Qing
AU - Reddy, Sangeetha M.
AU - Yu, Dihua
AU - Molldrem, Jeffrey J.
AU - Peoples, George E.
AU - Alatrash, Gheath
AU - Mittendorf, Elizabeth A.
N1 - Funding Information:
This work was supported by grants from the NCI (Cancer Center Support Grant P30CA016672 to MD Anderson Cancer Center; R00CA133244 to E.A. Mittendorf; T32CA009599 to V.A. Gall) and by awards from the Nancy Owens Memorial Foundation (E.A. Mittendorf), Pink Ribbons Project (E.A. Mittendorf), and the Jeanne F. Shelby Scholarship Fund (E.A. Mittendorf).
Publisher Copyright:
© 2017 AACR.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - Early-phase clinical trials evaluating CD8+ T cell–eliciting, HER2-derived peptide vaccines administered to HER2+ breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the mAb targeting the HER2 protein. Among 60 patients enrolled in clinical trials evaluating the E75 + GM-CSF and GP2 + GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here, we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. In vitro, increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein, an observation confirmed in two in vivo mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. On the basis of these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy.
AB - Early-phase clinical trials evaluating CD8+ T cell–eliciting, HER2-derived peptide vaccines administered to HER2+ breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the mAb targeting the HER2 protein. Among 60 patients enrolled in clinical trials evaluating the E75 + GM-CSF and GP2 + GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here, we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. In vitro, increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein, an observation confirmed in two in vivo mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. On the basis of these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy.
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U2 - 10.1158/0008-5472.CAN-16-2774
DO - 10.1158/0008-5472.CAN-16-2774
M3 - Article
C2 - 28819024
AN - SCOPUS:85031499088
SN - 0008-5472
VL - 77
SP - 5374
EP - 5383
JO - Cancer research
JF - Cancer research
IS - 19
ER -