While immune checkpoint blockade (ICB) (CTLA4/ PD1) therapy has resulted in durable responses in patients with advanced stage cutaneous melanoma, some patients do not benefit from this, due to... Show moreWhile immune checkpoint blockade (ICB) (CTLA4/ PD1) therapy has resulted in durable responses in patients with advanced stage cutaneous melanoma, some patients do not benefit from this, due to resistance mechanisms. This thesis aims to improve response of a subset of melanoma patients to immunotherapy. Firstly, mouse melanoma tumor models are developed that closely resemble some of the resistance mechanisms occurring in patient tumors, which are useful for research. Thereafter, a prognostic biomarker is used to identify the subset of melanoma patients that are unlikely to benefit from ICB therapy. It is then evaluated whether this subset of patients would benefit from combining histone deacetylase inhibitor with ICB. Despite encouraging pre-clinical results showing enhanced anti-tumor immune responses using this combination, this did not result in improved responses in the clinic. Furthermore, this thesis focuses on an immune cell subset, namely regulatory T cells (Tregs), which are known to suppress anti-tumor immune responses. Thus, their presence in the tumor microenvironment (TME) is detrimental to tumor cell killing. This thesis provides an increased understanding of the metabolic adaptation of Tregs to conditions in the TME and propose that targeting these adaptations might overcome the suppression by Tregs and enhance responses to immunotherapy. Show less
Stassen, R.C.; Mulder, E.E.A.P.; Mooyaart, A.L.; Francken, A.B.; Hage, J. van der; Aarts, M.J.B.; ... ; Grünhagen, D.J. 2023
Sentinel lymph node biopsy (SLNB) is recommended for patients with >pT1b cutaneous melanoma, and should be considered and discussed with patients diagnosed with pT1b cutaneous melanoma for the... Show moreSentinel lymph node biopsy (SLNB) is recommended for patients with >pT1b cutaneous melanoma, and should be considered and discussed with patients diagnosed with pT1b cutaneous melanoma for the purpose of staging, prognostication and determining eligibility for adjuvant therapy. Previously, the clinicopathologic and gene expression profile (CP-GEP, Merlin Assay (R)) model was developed to identify patients who can forgo SLNB because of a low risk for sentinel node metastasis. The aim of this study was to evaluate the clinical use and implementation of the CP-GEP model in a prospective multicenter study in the Netherlands. Both test performance and feasibility for clinical implementation were assessed in 260 patients with T1-T4 melanoma. The CPGEP model demonstrated an overall negative predictive value of 96.7% and positive predictive value of 23.7%, with a potential SLNB reduction rate of 42.2% in patients with T1-T3 melanoma. With a median time of 16 days from initiation to return of test results, there was sufficient time left before the SLNB was performed. Based on these outcomes, the model may support clinical decision-making to identify patients who can forgo SLNB in clinical practice. Show less
The aim of this thesis was to investigate if a text-mining tool is suitable for collecting real-world data from electronic health records to evaluate cancer treatments in clinical practice. By... Show moreThe aim of this thesis was to investigate if a text-mining tool is suitable for collecting real-world data from electronic health records to evaluate cancer treatments in clinical practice. By investigating a range of use cases including treatments of patients with renal cell carcinoma, hepatocellular carcinoma, melanoma, breast cancer, and COVID-19, it showed that the text-mining tool is a suitable method of data needed for the evaluation of treatment patterns, effectiveness, safety, prognostic factors, and guideline adherence. The discussion showed that enhancing the data quality and actively using real-world data for treatment evaluation regarding treatment policies are some of the next steps. Show less
Communication between cells is essential for the proper function of tissues in the human body. In cancer, this communication is disrupted. The signaling pathway initiated by Transforming Growth... Show moreCommunication between cells is essential for the proper function of tissues in the human body. In cancer, this communication is disrupted. The signaling pathway initiated by Transforming Growth Factor beta (TGF-beta) signaling molecules controls many processes in cells, including cell division, cell differentiation and cell migration. Dysregulation of TGF-beta signaling contributes to the formation and progression of many cancers. The inhibition of the TGF-beta signaling pathway is therefore an attractive anti-cancer therapy. Unfortunately, these therapies result in many side effects. The research described in this thesis aims to better understand TGF-beta signaling in different types of cancer. Through the development of new fluorescent tools, the activity and dynamics of TGF-beta signaling can be better studied in vitro and in vivo. In melanoma, the tumor microenvironment appeared to influence the effect of TGF-beta. In cervical cancer, TGF-beta activity levels could distinguish two subtypes of cervical cancer. In bladder cancer, a E3 ubiquitin ligase mediated a balance of BMP signaling, affecting bladder cancer progression. These studies all highlight the complexity of TGF-beta signaling and the need to fully understand TGF-beta signaling in different contexts to improve the use TGF-beta inhibition based therapies in the clinic. Show less
PurposeHeavy pigmentation is known to be a prognostic risk factor in uveal melanoma (UM). We analyzed whether genetic tumor parameters were associated with tumor pigmentation and whether... Show morePurposeHeavy pigmentation is known to be a prognostic risk factor in uveal melanoma (UM). We analyzed whether genetic tumor parameters were associated with tumor pigmentation and whether pigmentation should be included in prognostic tests.DesignRetrospective comparison of clinical, histopathological, and genetic features and survival in UM with different pigmentation.ParticipantsA total of 1058 patients with UM from a White European population with diverse eye colors enucleated between 1972 and 2021.MethodsCox regression and log-rank tests were used for survival analysis; the chi-square test and Mann–Whitney U test were used for correlation analysis.Main Outcome MeasuresUveal melanoma–related survival based on tumor pigmentation and chromosome status, correlation of tumor pigmentation with prognostic factors.ResultsThe 5-year UM-related mortality was 8% in patients with nonpigmented tumors (n = 54), 25% with lightly pigmented tumors (n = 489), 41% with moderately pigmented tumors (n = 333), and 33% with dark tumors (n = 178) (P < 0.001). The percentage of tumors with monosomy 3 (M3) or 8q gain increased with increasing pigmentation (31%, 46%, 62%, and 70% having M3 [P < 0.001], and 19%, 43%, 61%, and 63% having 8q gain [P < 0.001] in the 4 increasing pigment groups, respectively). BRCA-associated protein 1(BAP1) loss (known for 204 cases) was associated with increased tumor pigmentation (P = 0.001). Cox regression analysis on survival showed that when chromosome status and pigmentation were both included, pigmentation was not an independent prognostic indicator. Preferentially expressed antigen in melanoma (PRAME) expression was a significant prognostic marker in light tumors (P = 0.02) but not in dark tumors (P = 0.85).ConclusionsPatients with moderately and heavily pigmented tumors showed a significantly higher UM-related mortality than patients with unpigmented and light tumors (P < 0.001), supporting prior reports on the relation between increased tumor pigmentation and a worse prognosis. Although we previously showed that a dark eye color was associated with tumor pigmentation, we now show that the tumor’s genetic status (chromosome 3 and 8q/BAP1 status) is also related to tumor pigmentation. When pigmentation and chromosome 3 status are both included in a Cox regression analysis, pigmentation is not an independent prognostic factor. However, evidence from this and previous studies shows that chromosome changes and PRAME expression have a stronger association with survival when they occur in light tumors than in dark ones. Show less
This thesis aims to improve the treatment of patients with stage III melanoma. The first part describes different aspects of treatment with Talimogene Laherparepvec (T-VEC), a genetically modified... Show moreThis thesis aims to improve the treatment of patients with stage III melanoma. The first part describes different aspects of treatment with Talimogene Laherparepvec (T-VEC), a genetically modified herpes virus, which is used as oncolytic immunotherapy for skin and lymph node metastases in melanoma patients. We show that patients with a low tumor burden have the best outcomes, suggesting T-VEC should be used earlier on in the course of the disease. We present a prediction model, allowing a more accurate selection of patients for T-VEC monotherapy. Two studies focused on the use of T-VEC in clinical practice and the results allowed us to make recommendations on the use of PET/CT and dermoscopy during T-VEC treatment. Part two focuses on the value of surveillance and screening imaging in high-risk melanoma patients. We show that FDG-PET/CT is a valuable imaging tool to detect recurrence after complete resection of stage III disease, even shortly after surgery (before starting adjuvant therapy). Finally, we conclude that nodal staging with US as adjunct to SLNB is useful in the work- up of stage IIB/C melanoma, as it can lead to alterations in treatment and prevent unnecessary surgery. Show less
Background: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune... Show moreBackground: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. Methods: In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (& GE; 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (& GE; 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade & GE; 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. Discussion: Transplanting fecal microbiota to restore the patients' perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness. Show less
Single-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying... Show moreSingle-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying response rates. The purpose of this systematic review and meta-analysis was to investigate the efficacy and safety of T-VEC. Of 341 publications that were identified, eight studies with a total of 642 patients were included. In patients with stage IIIB-IVM1a, the pooled complete-and overall response rate (CRR and ORR) were 41% and 64%, respectively. In patients with stage IIIB-IVM1c, the pooled CRR and ORR were 30% and 44%, respectively. In patients with stage IVM1b and IVM1c, the pooled CRR and ORR were 4% and 9%, respectively. Adverse events (AEs) were seen in 41-100% of all patients and 0-11% of AEs were severe. In conclusion, single agent T-VEC achieves the highest response rates in patients with early metastatic melanoma and is well-tolerated with generally only mild toxicities. Show less
Death in all types of melanomas is generally caused by metastasis. Uveal melanoma (UM) is the most common intraocular melanoma, there are currently no (patient-derived) animal models that... Show moreDeath in all types of melanomas is generally caused by metastasis. Uveal melanoma (UM) is the most common intraocular melanoma, there are currently no (patient-derived) animal models that faithfully recapitulate metastatic dissemination of UM. Here we generate embryonic zebrafish models for both the primary and disseminated stage of ocular melanoma. In doing so we can recapitulate the etiology of cancer in its totality. Subsequently, we developed a patient-derived zebrafish xenograft (zf-PDX) model, using spheroid cultures generated from metastatic and primary UM tissues. Harnessing this versatile model, we reveal high sensitivity of circulating UM cells to ferroptosis induction in vivo by Erastin and RSL3, implicating ferroptosis as a new potential therapy in metastatic UM.Increased melanin levels in cutaneous melanoma are associated with decreased patient survival. Melanin levels in primary uveal melanoma patient cells positively correlate with their metastatic potential in zebrafish. Modulation of melanin levels of pan-melanoma cells results in enhanced/reduced metastatic potential upon increased or decreased melanin levels, respectively. Melanin depletion sensitizes melanoma cells to ferroptosis inducers in zebrafish leading to a decreased metastatic burden. Collectively, our data identify melanin biosynthetic enzymes as potential future target to treat melanoma and show that melanin protects metastasizing melanoma cells from ferroptosis. Show less
Although clinical aspects of melanoma have been extensively studied, the literature largely concerns relatively healthy 20-70 years old patients. Special populations, such as the elderly, children,... Show moreAlthough clinical aspects of melanoma have been extensively studied, the literature largely concerns relatively healthy 20-70 years old patients. Special populations, such as the elderly, children, patients with multiple primary melanoma and those with familial melanoma, are frequently excluded from clinical studies. The studies presented in this thesis were aimed to assess prognostic factors and management of patients with clinically localized melanoma, in particular among the aforementioned special populations. Show less
Rietbergen, D.D.D.; Arias-Bouda, L.M.P.; Hage, J.A. van der; Olmos, R.A.V. 2021
Introduction and objectives: To evaluate the migration of Tc-99m-tilmanocept from the injection site (IS) as well as the uptake in sentinel nodes (SNs) and non-SNs for lymphatic mapping in patients... Show moreIntroduction and objectives: To evaluate the migration of Tc-99m-tilmanocept from the injection site (IS) as well as the uptake in sentinel nodes (SNs) and non-SNs for lymphatic mapping in patients with breast cancer and melanoma, scheduled for SN biopsy after interstitial tracer administration.Materials and methods: For 29 primary tumours in 28 patients (mean age: 62y, range: 45-81y) scheduled for SN biopsy planar images were acquired 10 and 120 min after administration of 74 MBq Tc-99m-tilmanocept, in order to evaluate lymphatic drainage as well as uptake ratios between injection site (IS), SN and non-SN. SPECT/CT was performed immediately after delayed planar images to enable anatomical lymph node localization.Results: SNs were visualized in all patients (100%) with drainage to 34 basins. Uptake in non-SNs was perceived in 16 basins (47%). Number of SNs was concordant between early and delayed images in all basins excepting five (86%). In 24 patients tracer migrated to one lymph node basin (LNB), in three to 2 and in one to 4. When IS was included (n = 29) on image, IS/SN ratio could be measured per LNB. The IS/SN ratio at 2 h compared to 15 min decreased with an average of 66% (range: 15-96%). SN/non-SN 2 h ratio in LNBs with visible non-SNs averaged 6.6 (range: 2.3-15.6). In 9 patients with two SNs SN1/SN2 ratio averaged 1.9 on delayed images. At histopathology, SNs were found to be tumour positive in 7 basins (20%).Conclusion: Tc-99m-tilmanocept appears to meet the requirements for improved SN imaging in breast cancer and melanoma on the basis of early and persistent SN visualization frequently accompanied by no or markedly less non-SN uptake.This is associated to rapid migration from the injection site together with increasing SN uptake and retention as expressed by decreasing IS/SN and persistently high SN/non-SN ratios. Further head-to-head comparison of Tc-99m-tilmanocept with standard SN radiotracers in larger series of patients is necessary. (C) 2020 Sociedad Espanola de Medicina Nuclear e Imagen Molecular. Published by Elsevier Espana, S.L.U. All rights reserved. Show less
Mucosal melanomas are rare and only a small portion bear BRAF mutations while cutaneous melanomas have a much higher prevalence and often harbor BRAF mutations. We present two cases in which, after... Show moreMucosal melanomas are rare and only a small portion bear BRAF mutations while cutaneous melanomas have a much higher prevalence and often harbor BRAF mutations. We present two cases in which, after a malignant melanocytic mucosal lesion with a BRAF mutation was found, the primary cutaneous source was identified and clonality confirmed between the lesions. In both cases, primary lesions occurred on the scalp, an often-overlooked site. Both lesions showed signs of regression implying that in due time these lesions could have been fully regressed and might never have been detected. In that case, the metastatic mucosal lesion would erroneously be identified as a BRAF-mutated mucosal melanoma. These cases give warrant; a careful dermatological inspection should be instigated when confronted with a BRAF-mutated mucosal melanoma. We hypothesize that some BRAF-mutated mucosal melanomas might actually represent metastases of regressed cutaneous melanomas. Show less
Background: Patients with synchronous clinical stage III melanoma can present with primary melanoma lesions, locally recurrent melanoma or in-transit metastases. Neoad-juvant ipilimumab plus... Show moreBackground: Patients with synchronous clinical stage III melanoma can present with primary melanoma lesions, locally recurrent melanoma or in-transit metastases. Neoad-juvant ipilimumab plus nivolumab induces high pathologic response rates and an impressive relapse-free survival in patients with nodal macroscopic stage III melanoma. Whether primary site melanoma and in-transit metastases respond similarly to lymph node metastases with neoadjuvant immunotherapy is largely unknown. Such data would clarify whether surgical excision of these melanoma lesions should be performed before neoadjuvant therapy or whether it could be deferred and performed in conjunction with lymphadenectomy following neoadjuvant immunotherapy. Patients: Patients with synchronous clinical stage III melanoma were identified from the OpA-CIN, OpACIN-neo and PRADO neoadjuvant trials, where all patients were treated with ipi-limumab plus nivolumab. An additional case treated outside those clinical trials was included. Results: Seven patients were identified; six patients had a concordant response in primary site melanoma lesions or in-transit metastasis and the lymph node metastases. One patient had concordant progression in both the primary and nodal tumour lesions and developed stage IV disease during neoadjuvant treatment, and thus, no resection was performed. Conclusion: Pathologic response following neoadjuvant ipilimumab plus nivolumab in pri-mary site melanoma lesions or in-transit metastasis is concordant with a response in the lymph node metastases, indicating that there may be no need to perform upfront surgery to these melanoma lesions prior to neoadjuvant treatment. (c) 2021 Elsevier Ltd. All rights reserved. Show less
Background Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been... Show moreBackground Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. Methods Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. Results A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. Conclusions Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families. Show less
A type I immune response is crucial for adequate tumor eradication by the immune system. However, tumors often gain evasion mechanisms that create barriers to the generation or effectiveness of a... Show moreA type I immune response is crucial for adequate tumor eradication by the immune system. However, tumors often gain evasion mechanisms that create barriers to the generation or effectiveness of a type I immune response. Among these barriers is the suppression of effective T cell priming and the inhibition of proper T cell infiltration and function in tumors. At present, the only therapies to target these barriers are focused on direct inhibition of T cell function by the tumor, through checkpoint molecules. These therapies are thus dependent on an existing type I response, and are generally not successful when tumors have insufficient T cells primed or infiltrated. This thesis has revealed ways to improve T cell priming and the infiltration of T cells in tumors. Show less
Melanoma is the most aggressive and lethal type of skin cancer since it has the ability to spread to other organs in the body making it harder to control the disease.In this thesis, we aim to... Show moreMelanoma is the most aggressive and lethal type of skin cancer since it has the ability to spread to other organs in the body making it harder to control the disease.In this thesis, we aim to explore the degree to which epigenetics play a role in melanoma, namely, inherited and acquired epigenetic alterations in melanoma susceptibility and development. Show less
Background: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced... Show moreBackground: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer.Material and methods: Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines.Results: A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7vs. 89.8, difference (diff) = -5.80,p=.005), role (83.5vs.90, diff = -5.97,p=.02), cognitive (83.7vs.91.9, diff = -8.05,p=.001), and social functioning (86.5vs.95.1, diff = -8.49,p= <.001) and had a higher symptom burden of fatigue (23.0vs.15.5, diff = 7.48,p=.004), dyspnea (13.3vs.6.7, diff = 6.47p=.02), diarrhea (7.9vs.4.0, diff = 3.78,p=.04), and financial impact (10.5vs.2.5, diff = 8.07,p=.001) than matched controls. Group differences were indicated as clinically relevant.Discussion: Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care. Show less
In summary, this thesis focused on the understanding the underlying mechanisms driving TNBC metastatic progression. We established DUB activity profiling methods and identified UCHL1 as a candidate... Show moreIn summary, this thesis focused on the understanding the underlying mechanisms driving TNBC metastatic progression. We established DUB activity profiling methods and identified UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis. Importantly, we found UCHL1 activity inhibitor as a potential drug for TNBC therapy and developed UCHL1 activity-based probe. For vemurafenib-resistance melanoma, we provided insights that targeting TGFβ signaling may help to overcome drug resistant phenotype. Show less
Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between... Show moreEpidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 x 10(-06)) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 x 10(-04)) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression. Show less
The aim of the research described in this thesis was to gain a better understanding of the role of the different immune cells and the different FcR on their cell surface, in antibody therapy and... Show moreThe aim of the research described in this thesis was to gain a better understanding of the role of the different immune cells and the different FcR on their cell surface, in antibody therapy and to investigate whether the effectiveness of the tumor-killing mechanisms, activated by the antibodies, can be improved. First, we investigated the role of FcR in various immune responses using a genetically modified mouse, in which all FcR were missing. After defining that role, we studied antibody therapy in a mouse model for melanoma in two different ways: on the one hand, after vaccination using a viral vector that expressed a melanoma antigen, on the other hand, by injecting a melanoma-specific antibody in combination with other substances that activate the immune system. Show less
