Neutrophils are the most abundant leukocytes in the circulation, and have been regarded as first line of defence in the innate arm of the immune system. Thereby, the ability to migrate is essential for the functions of neutrophils. Directed migration in a gradient of chemotactic stimuli enables these cells to rapidly find the site of an infection and destroy the invading pathogens. However, excessive and persistent infiltration of neutrophils into tissues plays a role in multiple disease such as cancer. Neutrophils infiltrating tumors contribute to cancer progression and lead to a poor prognosis which makes neutrophil migration a potential target for cancer therapies.

This dissertation addresses the quantification and targeting of neutrophil migration in human and mouse cancers as a novel parameter for potential clinical applications. Thereby, two cancer types, melanoma and acute myeloid leukemia (AML) were investigated. To study the migration of murine neutrophils in melanoma, advanced in vivo and in vitro imaging techniques were performed. The recruitment of neutrophils to melanoma sites in vivo was examined using intravital imaging. In this regard, neutrophils displayed a highly oriented and increased migration towards melanoma cells and massively infiltrated tumors. In order to investigate neutrophil motility phenotypes in more detail, two in vitro migration assays were established. First the migration behavior of neutrophils in response to different stimuli from control BL/6 mice and from tumor bearing mice was studied. Here, neutrophils from tumor bearing mice displayed decreased migration and unresponsiveness to the stimuli compared to control cells. In a next step, an in vitro co-cultivation assay of cutaneous melanoma cells (CM) and neutrophils was established. This assay revealed interesting insight into the reciprocal interplay of both cells. It was shown that peritumoral neutrophils migrate with a significantly increased speed and directness towards cancer cells and infiltrate them compared to intratumoral neutrophils. Furthermore, neutrophils co-cultured with melanoma cells exhibited a high cell death rate and significantly promoted cancer growth. Based on the protumor role of the neutrophils, the next approach was to stop neutrophils from infiltrating the tumors. For this a large library with 1,000 compounds was screened and the ability of these compounds to decrease the directed motility of neutrophils towards cancer cells was analysed. Three promising compounds were identified and validated in more extensive experiments.

A second compound screen with further 1,000 compounds was performed with human neutrophils. Here, the ability of the compounds to interfere with N-Formylmethionyl-leucyl-phenylalanine (fMLP) stimulated migration was examined. Because fMLP stimulated neutrophils migrate at a very high speed and conventional microscopes do not allow high throughput (HT) screening of fast moving cells, a novel multi-lens video microscope, the ComplexEye, was introduced. It was demonstrated, that the ComplexEye respresents a comparable optical resolution and performance as conventional video microscopes. Using ComplexEye, 1,000 compounds were screened in HT and several interesting compounds modifying the speed and/or morphology of neutrophils were identified.

Furthermore, neutrophil migration profiles of patients with newly diagnosed AML and patients before and up to 18 months after hematopoietic cell transplantation (HCT) were analysed in a standardised in vitro assay. In this respect, neutrophils from newly diagnosed AML patients revealed pathological migration profiles and morphologies that started to normalize in remission. In addition, abnormal migration behaviors fully normalized after HCT and the patients adopted donor-like neutrophil migration phenotypes.

In summary, the present study provides evidence that the investigation and targeted modulation of neutrophil motility in cancer plays a very important role and may lead to future therapeutic approaches in cancer research.