Purpose: The tumor-associated self-antigen p53 is commonly overexpressed in cancer, including colorectal cancer, and can serve as a target for immunotherapy. The safety and immunogenicity of a p53 synthetic long peptide (p53-SLP) vaccine were investigated in patients treated for metastatic colorectal cancer. Experimental Design:Ten patients were vaccinated twice with a set of 10 overlapping p53-SLP in a phase I/II trial. Both the safety and the breadth, magnitude, and polarization of vaccineinduced p53-specificTcells was evaluated in blood samples drawn before and after vaccination by IFN-g enzyme-linked immunospot, proliferation, cytokine secretion, and multiparameter flow cytometry. The migratory capacity of p53-specificT cells was evaluated by assessing their presence in a biopsy of the second vaccination site. Results: Toxicity was limited to grade 1/2, mostly at the vaccination site. p53-specific T-cell responses were induced in 9 of 10 colorectal cancer patients as measured by IFN-g enzymelinked immunospot, proliferation, and cytokine bead array. In 6 of 9 tested patients, p53-specific T-cell reactivity persisted at least 6 months. Furthermore, p53-specific T cells isolated from the vaccination site were characterized as CD4 + T cells producing bothT-helper types 1and 2 cytokines on stimulation with p53 peptide and p53 protein. Multiparameter flow cytometry revealed that only a minor population of the p53-specific CD4 + Tcells was optimally polarized. Conclusions: The p53-SLP vaccine is safe and capable to induce p53-specificT-cell responses in patients treated for colorectal cancer. New trials should focus on improving the polarization of the p53-SLP vaccine-induced T-cell response.

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 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 chemotherapytreated 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.

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Here, we critically evaluated the knowledge on cutaneous melanoma (CM) and uveal melanoma (UM). Both cancer types derive from melanocytes that share the same embryonic origin and display the same cellular function. Despite their common origin, both CM and UM display extreme differences in their genetic alterations and biological behavior. We discuss the differences in genetic alterations, metastatic routes, tumor biology, and tumor-host interactions in the context of their clinical responses to targeted- and immunotherapy.

Purpose To determine the clinical impact of human leukocyte antigen (HLA) class I expression in irradiated and non-irradiated rectal carcinomas. Experimental design Tumor samples in tissue micro array format were collected from 1,135 patients. HLA class I expression was assessed after immunohistochemical staining with two antibodies (HCA2 and HC10).Results Tumors were split into two groups: (1) tumors with >50% of tumor cells expressing HLA class I (high) and (2) tumors with ·50% of tumor cells expressing HLA class I (low). No diVerence in distribution or prognosis of HLA class I expression was found between irradiated and nonirradiated patients. Patients with low expression of HLA class I (15% of all patients) showed an independent signiWcantly worse prognosis with regard to overall survival and disease-free survival. HLA class I expression had no eVect on cancer-speciWc survival or recurrence-free survival. Conclusions Down-regulation of HLA class I in rectal cancer is associated with poor prognosis. In contrast to our results, previous reports on HLA class I expression in colorectal cancer described a large population of patients with HLA class I negative tumors, having a good prognosis. This diVerence might be explained by the fact that a large proportion of HLA negative colon tumors are microsatellite instable (MSI). MSI tumors are associated with a better prognosis than microsatellite stable (MSS). As rectal tumors are mainly MSS, our results suggest that it is both, oncogenic pathway and HLA class I expression, that dictates patient's prognosis in colorectal cancer. Therefore, to prevent confounding in future prognostic analysis on the impact of HLA expression in colorectal tumors, separate analysis of MSI and MSS tumors should be performed.

Chemokines and their receptors are implicated in formation of colorectal cancer metastases. Especially CXCR4 is an important factor, determining migration, invasiveness, metastasis and proliferation of colorectal cancer cells. Object of this study was to determine expression of CXCR4 in tumor tissue of colorectal cancer patients and associate CXCR4 expression levels to clinicopathological parameters. Levels of CXCR4 expression of a random cohort of patients, who underwent primary curative resection of a colorectal carcinoma, were retrospectively determined by quantitative real-time RT-PCR and semi-quantitative analyses of immunohistochemical stained paraffin sections. Expression levels were associated to clinicopathological parameters. Using RT-PCR we found that a high expression of CXCR4 in the primary tumor was an independent prognostic factor for a poor disease free survival (p = 0.03, HR: 2.0, CI = 1.1–3.7). Immunohistochemical staining showed that nuclear distribution of CXCR4 in the tumor cells was inversely associated with disease free and overall survival (p = 0.04, HR: 2.6, CI = 1.0–6.2), while expression in the cytoplasm was not associated with prognosis. In conclusion, our study showed that a high expression of nuclear localized CXCR4 in tumor cells is an independent predictor for poor survival for colorectal cancer patients.

As many different genetic alterations in chondrosarcoma have been identified, it is of the utmost importance to classify druggable targets that may improve the prognosis of chondrosarcoma patients. In recent years an increased number of trials evaluating targeted therapies are being conducted. As chondrosarcoma is an orphan disease consequently all studies are performed with small numbers of patients. The results of clinical studies so far have been largely disappointing. Therapeutic intervention studies of these new targets emerging from preclinical studies are of highest importance to improve prognosis of chondrosarcoma patients with advanced disease.

Purpose: We isolated a subline (CC531M) from the CC531S rat colon carcinoma cell line, which grows and metastasizes much more rapidly than CC531S. We found, using RNA expression profiling, that one of the major changes in the CC531M cell line was a 5.8-fold reduction of the chemokine CXCL5. The purpose of this study was to determine the effect of CXCL5 expression on colorectal tumor growth and metastasis. Experimental Design: CC531 clones were generated with either knockdown or restored expression of CXCL5. These clones were inoculated in the liver of rats. In addition, in two independent cohorts of colorectal cancer patients, the level of CXCL5 expression was determined and associated to clinical variables. Results: Knockdown of CXCL5 expression in CC531S resulted in rapid tumor growth and increased number of metastasis, whereas restored expression of CXCL5 in CC531M resulted in a return of the ''mild'' tumor growth pattern of the parental cell line CC531S. In vitro, no difference was found in proliferation rate between clones with either high or low expression of CXCL5, suggesting that environmental interactions directed by CXCL5 determine tumor outgrowth. Finally, the importance of our findings was established for patients with colorectal cancer. We found that low expression of CXCL5 was significantly associated with poor prognosis for colorectal cancer patients. CXCL5 showed a trend (P = 0.05) for a positive correlation with intratumoral CD8 + T-cell infiltration, suggesting a possible explanation for the observed poorer prognosis. Conclusions: Our results show that CXCL5 is important in growth and development of colorectal cancer, implicating a future role in both cancer therapy and diagnosis.Colorectal cancer is one of the three leading causes of cancerrelated death among men and women in the western world (1, 2). Despite curative surgical resection of the primary tumor, 40% to 50% of the patients ultimately die of metastases (3). Tumor growth and metastasis result from a complex cascade of biological processes. Therefore, knowing key factors in these processes is crucial to design new treatment modalities.In a previous paper, we reported the in vivo selection of an aggressive rat colorectal cell line (CC531M) from the welldescribed CC531S cell line (4, 5). The present study was initiated to identify factors that contribute to rapid growth and metastatic capacity of CC531M. In this study, we focus on the chemokine CXCL5.CXCL5 is a member of the subfamily of lipopolysacharideinducible ELR + CXC chemokines (6). It functions, mainly through interaction with the CXCR2 receptor, both as a chemoattractant and as an angiogenic factor (7 -10). CXCL5 is expressed in the epithelial cells of the colon and overexpressed in colorectal cancer (11,12). It has been reported that CXCL5 plays a role in development and metastasis of several cancer types (13 -15). CXCL5 contributes to the in vivo growth and angiogenic potential of non -small cell lung cancer. Homogenates of human non -small cell lung cancer specimens...