title: Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells.
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
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Deepak
authors.initials: D
authors.lastname: Mittal
authors.affiliation: Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.
authors.forename: Franco
authors.initials: F
authors.lastname: Caramia
authors.affiliation: Service de Biostatistique et d'Epidemiologie, Gustave Roussy, Villejuif, France. INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.affiliation: Department of Oncology, Helsinki University Central Hospital and Helsinki University, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Department of Oncology, Tampere University Hospital and Tampere University, Tampere, Finland.
authors.forename: Pirkko-Liisa
authors.initials: PL
authors.lastname: Kellokumpu-Lehtinen
authors.affiliation: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium.
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.affiliation: Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. Mark.Smyth@qimrberghofer.edu.au.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000098546:Interleukin-21; C508053:ERBB2 protein, human