The first part of this thesis provides insight in prognostic markers in VSCC to refine clinicopathological risk assessment. One of the most frequently described risk factors for recurrent disease... Show moreThe first part of this thesis provides insight in prognostic markers in VSCC to refine clinicopathological risk assessment. One of the most frequently described risk factors for recurrent disease is the minimal peripheral surgical margin. In order to improve the quality of future studies and clinical recommendations, we provided a practical guideline on how to uniformly measure this margin in chapter 2. We also determined the clinical relevance of the molecular classification of VSCC based on immunohistochemical staining for p16 and p53. In chapter 3 we described the immunohistochemical characterization of these molecular subtypes to aid their detection in routine clinical practice. We utilized this approach to show the difference in clinical outcome between the three distinct molecular subtypes of VSCC in chapter 4.The second part of this thesis contains studies on the tumor microenvironment as a first step towards immunotherapy for VSCC. An overview of the literature concerning immunity in VSCC at the start of our studies is provided in chapter 5. Subsequently, we interrogated the TME of different VSCC subtypes in chapter 6, and showed that high infiltration of CD4+ T cells is important for clinical outcome, irrespective of the molecular subtype of VSCC. In chapter 7 we performed an in-depth analysis on the TME based on RNA profiles and showed that highly T cell infiltrated VSCC are potentially eligible candidates for immunotherapy. In chapter 8 we exploited the expression of CD39 by CD4+ and CD8+ T cells as a marker to identify tumor specific T cells. Finally, in chapter 9 the general aspects and relevance of the studies mentioned in this thesis are combined, discussed, and placed in a broader perspective with suggestions for future research. Show less
There is a pending need for prognostic and predictive biomarkers in the treatment of patients with colorectal cancer.This thesis describes the prognostic and predictive application of the tumor... Show moreThere is a pending need for prognostic and predictive biomarkers in the treatment of patients with colorectal cancer.This thesis describes the prognostic and predictive application of the tumor-stroma ratio (TSR) in colorectal cancer, focusing on expanding current clinical-pathological standards and combining TSR with other diagnostic parameters. The TSR is a microscopy scoring method performed on hematoxylin-eosin stained tissue slides used for routine pathology assessment, and has proven to be a robust prognostic maker. Here, we investigate whether the TSR also exhibits predictive value with regard to adjuvant targeted therapy in stage II and III colon cancer. Moreover, exploring the value of collagen fiber organization in the intratumoral stroma, as well as combining this parameter with the TSR. Finally, expanding the application of the TSR with radiological diagnostics in rectal cancer. Assessing is there is a correlation between TSR and apparent diffusion coefficient values obtained from diagnostically performed MRI-DWI scans, in order to determine if there is potential with regards to neoadjuvant treatment choices or patient follow-up. Show less
Tumors are complex ecosystems containing not just cancer cells, but a large variety of cell types, including immune cells. Moreover, tumors have a systemic influence: they can signal long distances... Show moreTumors are complex ecosystems containing not just cancer cells, but a large variety of cell types, including immune cells. Moreover, tumors have a systemic influence: they can signal long distances using soluble molecules and hijack non-neoplastic cells (such as immune cells) in distant organs for their own benefit, thus maximising their metastatic potential. The phenotype of immune cells in tumors and in systemic environments is therefore a key determinant of cancer progression and response to therapy.This thesis aims to understand what governs the tumor-immune ecosystem. We argue that cancer-intrinsic genetic aberrations have a dominant role in determining the tumor immune contexture, as well as systemic inflammatory activation. Understanding the intricate connection between the genetics of breast cancer and anti-tumor immune responses will help develop personalised immune intervention strategies for cancer, tailored to the genetic makeup of a patient’s tumor. Furthermore, we examine in detail the role of neutrophils in cancer-induced systemic inflammation, and how they influence the progression and spread of breast cancer. While tumors can be highly heterogeneous in nature, we show that neutrophils themselves also have a tremendous phenotypic diversity. Mapping this heterogeneity in neutrophil phenotypes may help to utilise these cells in cancer immunotherapy. Show less
