Improved treatment of breast cancer with anti-HER2 therapy requires interleukin-21 signaling in CD8+ T cells

Mittal, Deepak, Caramia, Franco, Michiels, Stefan, Joensuu, Heikki, Kellokumpu-Lehtinen, Pirkko-Liisa, Sotiriou, Christos, Loi, Sherene and Smyth, Mark J. (2016) Improved treatment of breast cancer with anti-HER2 therapy requires interleukin-21 signaling in CD8+ T cells. Cancer Research, 76 2: 264-274. doi:10.1158/0008-5472.CAN-15-1567


Author Mittal, Deepak
Caramia, Franco
Michiels, Stefan
Joensuu, Heikki
Kellokumpu-Lehtinen, Pirkko-Liisa
Sotiriou, Christos
Loi, Sherene
Smyth, Mark J.
Title Improved treatment of breast cancer with anti-HER2 therapy requires interleukin-21 signaling in CD8+ T cells
Formatted title
Improved treatment of breast cancer with anti-HER2 therapy requires interleukin-21 signaling in CD8+ T cells
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
1538-7445
Publication date 2016-01-15
Year available 2016
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-15-1567
Open Access Status Not Open Access
Volume 76
Issue 2
Start page 264
End page 274
Total pages 11
Place of publication Philadelphia, PA United States
Publisher American Association for Cancer Research
Collection year 2017
Language eng
Formatted abstract
The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2+ breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8+ T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4+ T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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