Tumor immune escape mechanisms are being regarded as suitable targets for tumor therapy. Among these, tryptophan catabolism plays a central role in creating an immunosuppressive environment, leading to tolerance to potentially immunogenic tumor antigens. Tryptophan catabolism is initiated by either indoleamine 2,3-dioxygenase (IDO-1/-2) or tryptophan 2,3-dioxygenase 2 (TDO2), resulting in biostatic tryptophan starvation and l-kynurenine production, which participates in shaping the dynamic relationship of the host’s immune system with tumor cells. Current immunotherapy strategies include blockade of IDO-1/-2 or TDO2, to restore efficient antitumor responses. Patients who might benefit from this approach are currently identified based on expression analyses of IDO-1/-2 or TDO2 in tumor tissue and/or enzymatic activity assessed by kynurenine/tryptophan ratios in the serum. We developed a monoclonal antibody targeting l-kynurenine as an in situ biomarker of IDO-1/-2 or TDO2 activity. Using Tissue Micro Array technology and immunostaining, colorectal and breast cancer patients were phenotyped based on l-kynurenine production. In colorectal cancer l-kynurenine was not unequivocally associated with IDO-1 expression, suggesting that the mere expression of tryptophan catabolic enzymes is not sufficiently informative for optimal immunotherapy.

The pathophysiological mechanisms that drive the development and progression of epithelial ovarian cancer remain obscure. Recently, we identified TCEAL7 as a transcriptional regulatory protein often downregulated in epithelial ovarian cancer. However, the biological significance of such downregulation in cancer is not currently known. Here, we show that TCEAL7 is downregulated frequently in many human cancers and that in immortalized human ovarian epithelial cells this event promotes anchorageindependent cell growth. Mechanistic investigations revealed that TCEAL7 associates with cyclin D1 promoter containing Myc E-box sequence and transcriptionally represses cyclin D1 expression. Moreover, downregulation of TCEAL7 promotes DNA-binding activity of Myc-Max, and upregulates the promoter activity of c-Myc-target gene, ornithine decarboxylase (ODC), whereas enhanced expression of TCEAL7 inhibits Myc-induced promoter activity of ODC. Our findings suggest that TCEAL7 may restrict ovarian epithelial cell transformation by limiting Myc activity. These results also suggest a potential, alternative mechanism by which c-Myc activity may be deregulated in cancer by the downregulation of TCEAL7.

Chronic inflammation underlies the basis for development and progression of cancers and a variety of other disorders, but what specifically defines its pathogenic nature remains largely undefined. Recent genetic and pharmacological studies in the mouse suggest that the immune modulatory enzyme indoleamine 2,3-dioxygenase (IDO), identified as an important mediator of immune escape in cancer, can also contribute to the development of pathology in the context of chronic inflammatory models of arthritis and allergic airway disease. IDO-deficient mice do not display spontaneous disorders of classical inflammation and small molecule inhibitors of IDO do not elicit generalized inflammatory reactions. Rather, in the context of a classical model of skin cancer that is promoted by chronic inflammation, or in models of inflammation-associated arthritis and allergic airway disease, IDO impairment can alleviate disease severity. Here we offer a survey of preclinical literature suggesting that IDO functions as a modifier of inflammatory states rather than simply as a suppressor of immune function. We propose that IDO induction in a chronically inflamed tissue may shape the inflammatory state to support, or in some cases retard, pathogenesis and disease severity.

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Introduction: Hormonotherapy (HT) of breast cancers (BC) is strongly limitated by the resistances. Because Rho proteins are key elements in the cross-talks between ERα and growth factors signaling, they may be involved in the response to HT. RhoB could play a negative role in oncogenesis but there is no valid data regarding RhoB expression in BC. Experimental results: Our data suggest that RhoB participates in the balance of expression of ERα. The inhibition of the expression of RhoB using two sequences of interfering RNA in hormonodependent cell lines (MCF-7, T47D, ZR75) and in anti-estrogen resistant cell lines (LCC2, LCC9), decreases the expression of ERα both at the protein and mRNA levels. Moreover, in Mouse Embryonic Fibroblasts and uteri collected from RhoB knock-out mice, a dramatic decrease of ERα expression is observed. We therefore investigated the expression level of RhoB and ERα in BC tumors. Patients and methods: A tissue microarray (TMA) was constructed from a cohort of 113 patients (pts) enrolled in a randomized trial for adjuvant tamoxifen (median follow-up: 249.9 months). RhoB, ERα, and PR expressions were measured by immunochemistry. Cut-off used for ERα and PR + was 10% of stained cells. The expression of RhoB was calculated with the IRS score. Correlation of RhoB expression score with clinically diagnostic and prognostic variables was assessed using Man Whitney and Spearman's rank tests. Univariate survival analysis was performed for disease free survival (DFS) by applying the log-rank test to RhoB expression levels stratified by median value. TMA results: 65 (58.6%) were grade I-II; 74(66.1%) were ERα+ and 59(52.7%) PR+; 23 (22.1%) presented lymphovascular (LV) invasion. 39 pts (34.8%) had lymph nodes (LN) +. Pts under tamoxifen (n=62) had a less favorable pathological profile regarding + LN (p=0.0039), pathological tumour size (p=0.0486) and number of mitoses (p=0.0556). Age, ERα/PR status, histological grade or type and LV invasion status were similar in the two groups. We found less RhoB IRS expression in pts with tumor grade III (median 8 [1;12]) than in grade I-II (median 9 [3;12], p=0.0142). RhoB IRS expression was much higher in ERa + tumors (median:10.5 [3;12]) than in ERa negative tumors (median=8 [1;12], p=0.0023). RhoB IRS score was not correlated with the presence or not of LV invasion (p=0.26), neither with the presence of LN invasion (p= 0.74). Furthermore, RhoB expression is i) strongly correlated with the % of expression of ERα (Spearman'sρ=0.3659; p = 0.001) and PR (Spearman's ρ=0.2544 ; p=0.0076) ii) inversely correlated with histologic size (Spearman's ρ= -0.2344 ; p = 0.0166) and with number of mitose (Spearman's ρ=-0.2009 ; p=0.0362). The DFS of pts with ERα + tumors under tamoxifen or not was not affected by the level of RhoB expression. Conclusion: The analysis of 113 human breast tumors allowed to confirm experimental results, demonstrating that RhoB expression is strongly correlated with ERα expression. The role of RhoB as a potential suppressor gene of tumours in BC and its role in the response to HT have then to be investigated further. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5146.