herceptin efficacy may require interlukin21 signalling in CD8+ Tcells

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augmenting IL21 signalling may make herceptin work better in more patients &
avoid resistance

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Cancer Res. 2016 Jan 7.
Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells.
Mittal D1, Caramia F2, Michiels S3, Joensuu H4, Kellokumpu-Lehtinen PL5, Sotiriou C6, Loi S7, Smyth MJ8.
Author information
1Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.
2Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
3Service de Biostatistique et d'Epidemiologie, Gustave Roussy, Villejuif, France. INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. Department of Oncology, Tampere University Hospital and Tampere University, Tampere, Finland.
4Department of Oncology, Helsinki University Central Hospital and Helsinki University, Helsinki, Finland.
5Department of Oncology, Tampere University Hospital and Tampere University, Tampere, Finland.
6Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium.
7Service de Biostatistique et d'Epidemiologie, Gustave Roussy, Villejuif, France. INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
8Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia. Mark.Smyth@qimrberghofer.edu.au.
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. Cancer Res; 76(2); 1-11. ©2015 AACR.
©2016 American Association for Cancer Research.