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      Concurrent infiltration by CD8 + T cells and CD4 + T cells is a favourable prognostic factor in non-small-cell lung carcinoma

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          Abstract

          The purpose of this study was to clarify the relationship between the number of tumour-infiltrating T lymphocytes and the clinicopathological features and clinical outcome in patients with non-small-cell lung cancer (NSCLC). Tissue specimens from 109 patients who underwent surgical resection for NSCLC were immunohistochemically analysed for CD4 and CD8 expression. Patients were classified into two groups according to whether their tumours exhibited a ‘high' or ‘low' level of CD8 + or CD4 + lymphocyte infiltration. Although the level of infiltration by CD8 + T cells alone had no prognostic significance, the survival rate for patients with both ‘high' CD8 + and ‘high' CD4 + T-cell infiltration was significantly higher than that for the other groups (log-rank test, P=0.006). Multivariate analysis indicated that concomitant high CD8 + and high CD4 + T-cell infiltration was an independent favourable prognostic factor ( P=0.0092). In conclusion, the presence of high levels of both CD8 + T cells and CD4 + T cells is a significant indicator of a better prognosis for patients with NSCLC, and cooperation between these cell populations may allow a significantly more potent antitumour response than either population alone.

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          Most cited references38

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          Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report.

          Lymphocytes extracted from freshly resected melanomas can be expanded in vitro and can often mediate specific lysis of autologous tumor cells but not allogeneic tumor or autologous normal cells. We treated 20 patients with metastatic melanoma by means of adoptive transfer of these tumor-infiltrating lymphocytes and interleukin-2, after the patients had received a single intravenous dose of cyclophosphamide. Objective regression of the cancer was observed in 9 of 15 patients (60 percent) who had not previously been treated with interleukin-2 and in 2 of 5 patients (40 percent) in whom previous therapy with interleukin-2 had failed. Regression of cancer occurred in the lungs, liver, bone, skin, and subcutaneous sites and lasted from 2 to more than 13 months. Toxic effects of interleukin-2 occurred, although the treatment course was short (five days); these side effects were reversible. It appears that in patients with metastatic melanoma, this experimental treatment regimen can produce higher response rates than those achieved with interleukin-2 administered alone or with lymphokine-activated killer cells. It is too early to determine whether this new form of immunotherapy can improve survival, but further trials seem warranted.
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            IL-10 inhibits cytokine production by activated macrophages.

            IL-10 inhibits the ability of macrophage but not B cell APC to stimulate cytokine synthesis by Th1 T cell clones. In this study we have examined the direct effects of IL-10 on both macrophage cell lines and normal peritoneal macrophages. LPS (or LPS and IFN-gamma)-induced production of IL-1, IL-6, and TNF-alpha proteins was significantly inhibited by IL-10 in two macrophage cell lines. Furthermore, IL-10 appears to be a more potent inhibitor of monokine synthesis than IL-4 when added at similar concentrations. LPS or LPS- and IFN-gamma-induced expression of IL-1 alpha, IL-6, or TNF-alpha mRNA was also inhibited by IL-10 as shown by semiquantitative polymerase chain reaction or Northern blot analysis. Inhibition of LPS-induced IL-6 secretion by IL-10 was less marked in FACS-purified peritoneal macrophages than in the macrophage cell lines. However, IL-6 production by peritoneal macrophages was enhanced by addition of anti-IL-10 antibodies, implying the presence in these cultures of endogenous IL-10, which results in an intrinsic reduction of monokine synthesis after LPS activation. Consistent with this proposal, LPS-stimulated peritoneal macrophages were shown to directly produce IL-10 detectable by ELISA. Furthermore, IFN-gamma was found to enhance IL-6 production by LPS-stimulated peritoneal macrophages, and this could be explained by its suppression of IL-10 production by this same population of cells. In addition to its effects on monokine synthesis, IL-10 also induces a significant change in morphology in IFN-gamma-stimulated peritoneal macrophages. The potent action of IL-10 on the macrophage, particularly at the level of monokine production, supports an important role for this cytokine not only in the regulation of T cell responses but also in acute inflammatory responses.
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              CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer.

              The pathophysiological significance of tumor infiltrating lymphocytes remains controversial. To clarify their role, we performed clinicopathological analysis of CD8+ T cells in 131 cases of human colorectal cancer. CD8+ T cells were classified into three groups by their localization: (a) those infiltrated within cancer cell nests; (b) those distributed in the cancer stroma; and (c) those present along the invasive margin (tumor-host interface). Of these, CD8+ T cells within cancer cell nests were most significantly associated with a better survival of patients by both mono- and multivariate analyses. The impact on survival was similar to that of Dukes' staging. Granzyme B+ cytoplasmic granules were detected in lymphocytes within cancer cell nests, confirming their activated, cytotoxic phenotype. CD8 and Ki-67 double immunohistochemistry confirmed higher proliferative activity of CD8+ T cells within cancer cell nests. Our data suggested that human colorectal cancer tissue was infiltrated by various numbers of T cells that had cytotoxic phenotype, contributing to a better survival of patients. This infiltration of colorectal cancer cell nests by CD8+ T cells could be a novel prognostic factor.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                0007-0920
                1532-1827
                24 January 2006
                30 January 2006
                : 94
                : 2
                : 275-280
                Affiliations
                [1 ]Surgical Oncology, Cancer Medicine, Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan
                [2 ]Department of Medicine, University of California Los Angeles, MRL-1551, 675 Charles E Young Drive South, Los Angeles, CA 90095, USA
                [3 ]Department of Surgical Pathology, Hokkaido University Hospital, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan;
                [4 ]Department of Thoracic Surgery, Minami-Ichijo Hospital, Minami-1, Nishi-13, Chuo-ku, Sapporo 060-0061, Japan
                Author notes
                [* ]Author for correspondence: hiraoka@ 123456ucla.edu
                Article
                6602934
                10.1038/sj.bjc.6602934
                2361103
                16421594
                da348592-3ae7-4c7f-8299-6470669f3123
                Copyright 2006, Cancer Research UK
                History
                : 06 September 2005
                : 07 November 2005
                : 30 November 2005
                Categories
                Molecular Diagnostics

                Oncology & Radiotherapy
                cd8+ t cells,prognostic factor,non-small-cell lung carcinoma,immunohistochemistry,cd4+ t cells

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