Articles: carcinoma-immunology.
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The extent to which T-cell-mediated immune surveillance is impaired in human cancer remains a question of major importance, given its potential impact on the development of generalized treatments of advanced disease where the highest degree of heterogeneity exists. Here, we report the first global analysis of immune dysfunction in patients with advanced hepatocellular carcinoma (HCC). Using multi-parameter fluorescence-activated cell sorting analysis, we quantified the cumulative frequency of regulatory T cells (Treg), exhausted CD4(+) helper T cells, and myeloid-derived suppressor cells (MDSC) to gain concurrent views on the overall level of immune dysfunction in these inoperable patients. ⋯ In dampening T-cell-mediated antitumor immunity, we hypothesized that these processes may facilitate HCC progression and thwart the efficacy of immunotherapeutic interventions. In testing this hypothesis, we showed that combined regimens to deplete Tregs, MDSC, and PD-1(+) T cells in patients with advanced HCC restored production of granzyme B by CD8(+) T cells, reaching levels observed in normal controls and also modestly increased the number of IFN-γ producing CD4(+) T cells. These clinical findings encourage efforts to restore T-cell function in patients with advanced stage disease by highlighting combined approaches to deplete endogenous suppressor cell populations that can also expand effector T-cell populations.
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With growing evidence on the role of inflammation in carcinogenesis, the presence of a systemic inflammatory response has been proposed as having prognostic significance in a wide range of cancers. The aim of the study was to assess the value of pretreatment neutrophil-to-lymphocyte ratio (NLR) in predicting disease-specific survival (DSS) in patients with oral cancer undergoing preoperative chemoradiotherapy. A cohort of 97 patients with locally advanced oral squamous cell carcinoma receiving preoperative chemoradiotherapy was retrospectively examined. ⋯ In univariate analysis, high pretreatment NLR (p = 0.018), positive perineural invasion (p < 0.001) and advanced pathologic TNM stage after neoadjuvant therapy (p < 0.001) were predictive of shorter DSS. In multivariate analysis, advanced pathologic TNM stage after neoadjuvant therapy (HR 1.71, 95 % CI 1.17-2.48, p = 0.005), positive perineural invasion (HR 3.67, 95 % CI 1.11-12.13, p = 0.033) and high pretreatment NLR (HR 10.37, 95 % CI 1.28-84.08, p = 0.029) remained independently associated with poor DSS. A high pretreatment NLR is a significant independent predictor of shorter DSS in patients with oral cancer receiving preoperative chemoradiotherapy.
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Systemic inhibition of the inflammatory enzyme cyclooxygenase (COX) 2 decreases the risk of breast cancer and its recurrence. However, the biology of COX-2 in the multicellular tumor microenvironment is poorly defined. ⋯ The data strongly support that, in addition to its angiogenic function, tumor cell COX-2 suppresses intratumoral cytotoxic CD8+ immune cell function, possibly through upregulation of immune checkpoints, thereby contributing to tumor immune escape. COX-2 inhibition may be clinically useful to augment breast cancer immunotherapy.
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Sorafenib, a multi-tyrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC). The present study was undertaken to determine whether the growth and metastasis of HCC were influenced in mice receiving sorafenib prior to implantation with tumors, and to investigate the in-vivo and in-vitro effect of sorafenib on natural killer (NK) cells. In sorafenib-pretreated BALB/c nu/nu mice and C57BL/6 mice, tumor growth was accelerated, mouse survival was decreased, and lung metastasis was increased. ⋯ Sorafenib significantly reduced the number of NK cells and inhibited reactivity of NK cells against tumor cells, in both tumor-bearing and tumor-free C57BL/6 mice. Sorafenib down-regulated the stimulatory receptor CD69 in NK cells of tumor-bearing mice, but not in tumor-free mice, and inhibited proliferation of NK92-MI cells, which is associated with the blocking of the PI3K/AKT pathway, and inhibited cytotoxicity of NK cells in response to tumor targets, which was due to impaired ERK phosphorylation. These results suggest immunotherapeutic approaches activating NK cells may enhance the therapeutic efficacy of sorafenib in HCC patients.