IL-15 enhances the anti-tumor activity of trastuzumab against breast cancer cells but causes fatal side effects in humanized tumor mice (HTM).
Cancer immunotherapy has been shown to enhance established treatment regimens. We evaluated the potential reinforcing effect of IL-15 in trastuzumab treated humanized tumor mice (HTM) which were generated by concurrent transplantation of neonatal NOD-scid IL2Rγnull mice with human hematopoietic stem cells (HSC) and HER2 positive breast cancer cells (metastasizing SK-BR-3, solid tumor forming BT474).We found that trastuzumab treatment efficacy mainly depends on the immediate anti-tumorigenic cellular effect which is significantly enhanced by tumor interacting immune cells upon cotransplantion of HSC. However, trastuzumab treatment caused elevated CD44 expression on tumor cells that metastasized into the lung and liver but did not hinder tumor cell dissemination into the bone marrow. Moreover, in a number of SK-BR-3-transplanted animals disseminated CD44high/CD24low tumor cells lost trastuzumab sensitivity. Concerning the FcγRIIIa polymorphism, trastuzumab treatment efficiency in HTM was higher in mice with NK-cells harboring the high affinity FcγRIIIa compared to those with low affinity FcγRIIIa. In contrast, IL-15 caused the strongest NK-cell activation in heterozygous low affinity FcγRIIIa animals. Although IL-15 enhanced the trastuzumab mediated tumor defense, an unspecific immune stimulation resulted in preterm animal death due to systemic inflammation. Overall, treatment studies based on "patient-like" HTM revealed critical and adverse immune-related mechanisms which must be managed prior to clinical testing.
Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany.
Anja K
AK
Wege
Institute of Pathology, University Hospital Regensburg, 93053 Regensburg, Germany.
Florian
F
Weber
MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC, USA.
Alexander
A
Kroemer
Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany.
Olaf
O
Ortmann
Institute of Genetics, Department of Biology, University of Erlangen-Nuremberg, 91058, Erlangen, Germany.
Falk
F
Nimmerjahn
Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany.
Gero
G
Brockhoff
D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005838:Genotype; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D056747:Immunomodulation / Q000187:drug effects; D019409:Interleukin-15 / Q000494:pharmacology*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011110:Polymorphism, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D017452:Receptors, IgG / Q000235:genetics; D000068878:Trastuzumab / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000074322:Antineoplastic Agents, Immunological; D018960:Hyaluronan Receptors; D019409:Interleukin-15; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; D000068878:Trastuzumab
IL-15; breast cancer; humanized tumor mice (HTM); immunomodulation; trastuzumab