This dissertation reports on the relation between the immune system, colorectal cancer and immunotherapy. In the first part, expression of HLA class I and expression of CXCL5 in colocectal cancer... Show moreThis dissertation reports on the relation between the immune system, colorectal cancer and immunotherapy. In the first part, expression of HLA class I and expression of CXCL5 in colocectal cancer was studied. Low expression of HLA class I in rectal tumors was associated with poor survival of rectal cancer patients. Low expression of CXCL5 in cancer cells was significantly associated with poor prognosis in a population of colorectal cancer patients and correlated with presence of intra-tumoral CD8+ T-cell infiltration. In the second part of this thesis we focused on induction of tumor specific T-cells. For immunotherapeutic purposes distinction should be made between microsatellite instable (MSI-H) and microsatellite stable (MSS) colorectal tumors, as MSI-H tumors express neo-antigens __foreign__ to the immune system while immunotherapy against MSS tumors depends on tumor associated __self__-antigens. We developed a methodology predicting immunogenic behavior of frameshift-mutated antigens present in MSI-H tumors that was based on accumulation and MHC class I presentation. This method can be used to develop cancer immunotherapy of patients at risk for MSI-H tumors. In the last two chapters we described safety and immunogenicity of a p53 synthetic long peptides vaccine combined with and without Interferon-alpha. Addition of IFN-_ to the p53-SLP_ vaccine significantly improved p53-specific after vaccination. Altogether this dissertation reports on the relation between the immune system, colorectal cancer and immunotherapy. This knowledge can be used to further optimize immunotherapeutic strategies to treat cancer patients. Show less
Speetjens, F.M.; Zeestraten, E.C.M.; Kuppen, P.J.K.; Melief, C.J.M.; Burg, S.H. van der 2011
This article elucidates current strategies of active immunotherapy for colorectal cancer patients with a focus on T-cell mediated immunotherapy. Poor prognosis of especially stage III and IV... Show moreThis article elucidates current strategies of active immunotherapy for colorectal cancer patients with a focus on T-cell mediated immunotherapy. Poor prognosis of especially stage III and IV colorectal cancer patients emphasizes the need for advanced therapeutic intervention. Here, we refer to clinical trials using either tumor cell-derived vaccines or tumor antigen vaccines with a special interest on safety, induced immune responses, clinical benefit and efforts to improve the clinical impact of these vaccines in the context of colorectal cancer treatment. Show less
Speetjens, F.M.; Zeestraten, E.C.M.; Kuppen, P.J.K.; Melief, C.J.M.; Burg, S.H. van der 2011
This article elucidates current strategies of active immunotherapy for colorectal cancer patients with a focus on T-cell mediated immunotherapy. Poor prognosis of especially stage III and IV... Show moreThis article elucidates current strategies of active immunotherapy for colorectal cancer patients with a focus on T-cell mediated immunotherapy. Poor prognosis of especially stage III and IV colorectal cancer patients emphasizes the need for advanced therapeutic intervention. Here, we refer to clinical trials using either tumor cell-derived vaccines or tumor antigen vaccines with a special interest on safety, induced immune responses, clinical benefit and efforts to improve the clinical impact of these vaccines in the context of colorectal cancer treatment. Show less
Interleukin-2 is an important activation factor for natural killer (NK) cells but its effect on NK cell matrix metalloproteinases (MMP) production and matrix degradation is less well investigated.... Show moreInterleukin-2 is an important activation factor for natural killer (NK) cells but its effect on NK cell matrix metalloproteinases (MMP) production and matrix degradation is less well investigated. We have used freshly isolated human NK cells and the IL-2-independent NK cell line, YT, to investigate the effects of IL-2 stimulation on NK cell invasion of Matrigel and on MMP expression and production. In YT cells, we found opposing early and late effects of IL-2 stimulation with an early (2 h) increase in MMP-9 protein level and enhanced migration in the Matrigel invasion assay and by 30 hours a decreased mRNA expression of MMP-2, MMP-9, MMP-13, MT3-MMP, and MT6-MMP. We also found a preculture period of 48 hours with IL-2 to negatively affect YT cell migration. We furthermore found that freshly isolated human NK cells Matrigel invasion was MMP-dependent and it increased in response to IL-2. Importantly, in freshly isolated human NK cells we did not see a downregulation of MMPs after 24 hours IL-2 stimulation, but instead a significant upregulation of MT6-MMP mRNA. Because of the cellular localisation of MT6-MMP, which ensures a focalized proteolytic activity, and its high expression compared with the other MMPs in freshly isolated human NK cells makes it of interest to study further. Show less
Purpose: We hypothesized that T-cell immune interaction affects tumor development and thus clinical outcome. Therefore, we examined the clinical impact of human leukocyte antigen (HLA) class I... Show morePurpose: We hypothesized that T-cell immune interaction affects tumor development and thus clinical outcome. Therefore, we examined the clinical impact of human leukocyte antigen (HLA) class I tumor cell expression and regulatory T-cell (Treg) infiltration in breast cancer. Experimental Design: Our study population (N = 677) is consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Formalin-fixed, paraffin-embedded tumor tissue was immunohistochemically stained using HCA2, HC10, and Foxp3 monoclonal antibodies. Results: HLA class I expression was evaluated by combining results from HCA2 and HC10 antibodies and classified into three groups: loss, downregulation, and expression. Remarkably, only in patients who received chemotherapy, both presence of Treg (P = 0.013) and higher HLA class I expression levels (P = 0.002) resulted in less relapses, independently of other variables. Treg and HLA class I were not of influence on clinical outcome in patients who did not receive chemotherapy. Conclusions: We showed that HLA class I and Treg affect prognosis exclusively in chemotherapy-treated patients and are therefore one of the few predictive factors for chemotherapy response in early breast cancer patients. Chemotherapy may selectively eliminate Treg, thus enabling CTLs to kill tumor cells that have retained HLA class I expression. As a consequence, HLA class I and Treg can predict response to chemotherapy with high discriminative power. These markers could be applied in response prediction to chemotherapy in breast cancer patients. Clin Cancer Res; 16(4); 1272-80. (C) 2010 AACR. Show less
