Several immunotherapeutic strategies for the treatment of cancer are under development. Two prominent strategies are adoptive cell transfer (ACT) of CTLs and modulation of CTL function with immune... Show moreSeveral immunotherapeutic strategies for the treatment of cancer are under development. Two prominent strategies are adoptive cell transfer (ACT) of CTLs and modulation of CTL function with immune checkpoint inhibitors or with costimulatory antibodies. Despite some success with these approaches, there remains a lack of detailed and quantitative descriptions of the events following CTL transfer and the impact of immunomodulation. Here, we have applied ordinary differential equation models to two photon imaging data derived from a B16F10 murine melanoma. Models were parameterised with data from two different treatment conditions: either ACT-only, or ACT with intratumoural costimulation using a CD137 targeted antibody. Model dynamics and best fitting parameters were compared, in order to assess the mode of action of the CTLs and examine how the CD137 antibody influenced their activities. We found that the cytolytic activity of the transferred CTLs was minimal without CD137 costimulation, and that the CD137 targeted antibody did not enhance the per-capita killing ability of the transferred CTLs. Instead, the results of our modelling study suggest that an antiproliferative effect of CTLs exerted upon the tumour likely accounted for the majority of the reduction in tumour growth after CTL transfer. Moreover, we found that CD137 most likely improved tumour control via enhancement of this antiproliferative effect, as well as prolonging the period in which CTLs were inside the tumour, leading to a sustained duration of their antitumour effects following CD137 stimulation. Show less
The study of immunity against Transporter Associated with Antigen Processing (TAP)-deficient cells led to the discovery of peptides presented by such TAP-deficient cells. Some of these peptides... Show moreThe study of immunity against Transporter Associated with Antigen Processing (TAP)-deficient cells led to the discovery of peptides presented by such TAP-deficient cells. Some of these peptides constituted antigens to Cytotoxic T-lymphocytes (CTL) and these CTL only recognized TAP-deficient cells but not normal cells. These peptides were called __T-cell epitopes associated with impaired peptide processing__ (TEIPP). Therefore, TEIPP corresponds to immunogenic peptides that are presented only in cases of processing deficiency and not by normal cells. The studies of TEIPP antigens thus far have revealed that these antigens are promising candidates for the combat of immune escaped tumors. However, several aspects about TEIPPs needed clarification: what are the processing pathways that lead to generation and presentation of TEIPP antigens; what is the mechanism behind the immunogenicity of TEIPP; what are the charac teristics of TEIPP peptides presented by non-classical Major Histocompatibility Complex class I (MHC-I) molecules. The studies presented in this thesis are focused on these topics Show less
Oliveira, C.C.; Querido, B.; Sluijter, M.; Derbinski, J.; Burg, S.H. van der; Hall, T. van 2011
This thesis describes six studies which characterized tumor-infiltrating leukocytes (TIL) in colorectal cancer. TIL have shown to be of importance in the natural anti-tumor immunity of cancer... Show moreThis thesis describes six studies which characterized tumor-infiltrating leukocytes (TIL) in colorectal cancer. TIL have shown to be of importance in the natural anti-tumor immunity of cancer patients. Chapter 1 gives an introductory overview of tumor immunology, TIL and colorectal cancer. In chapter 2 we describe the presence, location, and phenotype of tumor-infiltrating dendritic cells in colorectal cancer. With special attention to their association with other tumor-infiltrating immune cells, i.e. lymphocytes. Chapter 3 elaborates further on the role of tumor-infiltrating DC by evaluating whether there is an association between the presence and maturation status of tumor-infiltrating DC, T lymphocytes and clinical prognosis in patients with colorectal cancer. In chapter 4 NK cell infiltration in colorectal cancer is studied in relationship with loss of tumor MHC class I expression. In chapter 5 TIL were characterized in a case-control design, with tumors showing complete absence or normal expression of HLA class I. We further characterized TIL in a group of colorectal tumors displaying systemic P53 reactivity in chapter 6. Chapter 7 describes the technique of the multi-color immunohistochemical analysis, which we used to characterize the phenotype of TIL in the two preceding chapters. Chapter 8 Summary and Discussion. Show less
