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
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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