Abstract
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.
Highlights
Antigen-specific antibodies are the primary tool for individualized treatment of cancer patients
Further analyses of cell subsets revealed an increased proportion of B cells in the spleen of SK-BR-3 (Supplementary Figure S1A; average age 16 weeks post transplant) compared to BT474 transplanted mice (Supplementary Figure S1B; average age 23 weeks post transplant) which is due to the different time point of analyses
Trastuzumab significantly improves the overall outcome of breast cancer (BC) patients, a significant fraction of patients suffer from de-novo or acquired resistance
Summary
Antigen-specific antibodies are the primary tool for individualized treatment of cancer patients. Specific tumor targeting has a high curative potential and is typically associated with less systemic side effects compared to cytotoxic treatment regimens. The treatment of early and advanced HER2-positive breast cancer (BC) patients with trastuzumab (Herceptin®), a humanized monoclonal anti-HER2 antibody, results in both prolonged diseasefree and overall survival (DFS, OS). >50% of HER2-positive patients do not benefit due to of de-novo or acquired resistance [1]. Therapy failure has been attributed to cellular effects (e.g., inefficient trastuzumab binding or activation of alternate signaling pathways). On the other hand there is apparently an insufficient activation of immune effector cells, e.g., NK-cells and macrophages, which are thought to exert antibody-dependent cellular cytotoxicity (ADCC) [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
