Peripheral burst of tumor-specific cytotoxic T lymphocytes and infiltration of metastatic lesions by memory CD8+ T cells in melanoma patients receiving interleukin 12. (65/1358)

Systemic effects on T-cell-mediated antitumor immunity, on expression of T-cell adhesion/homing receptors, and on the promotion of T-cell infiltration of neoplastic tissue may represent key steps for the efficacy of immunological therapies of cancer. In this study, we investigated whether these processes can be promoted by s.c. administration of low-dose (0.5 microg/kg) recombinant human interleukin-12 (rHuIL-12) to metastatic melanoma patients. A striking burst of HLA-restricted CTL precursors (CTLp) directed to autologous tumor was documented in peripheral blood by a high-efficiency limiting dilution analysis technique within a few days after rHuIL-12 injection. A similar burst in peripheral CTLp frequency was observed even when looking at response to a single tumor-derived peptide, as documented by an increase in Melan-A/Mart-1(27-35)-specific CTLp in two HLA-A*0201+ patients by limiting dilution analysis and by staining peripheral blood lymphocytes (PBLs) with HLA-A*0201-melanoma antigen-A/melanoma antigen recognized by T cells (Melan-A/Mart)-1 tetrameric complexes. The CTLp burst was associated, in PBLs, with enhanced expression of T-cell adhesion/homing receptors CD11a/CD18, CD49d, CD44, and with increased proportion of cutaneous lymphocyte antigen (CLA)-positive T cells. This was matched by a marked increase, in serum, of soluble forms of the endothelial cell adhesion molecules E-selectin, vascular cell adhesion molecules (VCAM)-1 and intercellular adhesion molecules (ICAM)-1. Infiltration of neoplastic tissue by CDS+ T cells with a memory and cytolytic phenotype was found by immunohistochemistry in eight of eight posttreatment metastatic lesions but not in five of five pretreatment metastatic lesions from three patients. Increased tumor necrosis and/or fibrosis were also found in several posttherapy lesions of two of three patients in comparison with pretherapy metastases. These results provide the first evidence that rHuIL-12 can boost the frequency of circulating antitumor CTLp in tumor patients, enhances expression of ligand receptor pairs contributing to the lymphocyte function-associated antigen-1/ICAM-1, very late antigen-4/VCAM-1, and CLA/E-selectin adhesion pathways, and promotes infiltration of neoplastic lesions by CD8+ memory T cells in a clinical setting.  (+info)

Intranodal antitumor immunocyte infiltration in node-negative gastric cancers. (66/1358)

The status and role of immunocytes and dendritic cells in regional lymph nodes in patients with gastric cancer are examined in this study. Forty-nine patients with gastric cancer who underwent curative resection were enrolled in the present study. These patients had no lymph node metastases according to a histological examination. The infiltration of natural killer (NK) cells, dendritic cells, and MIB-1-positive immunocytes was investigated. Based on the Japanese Classification of Gastric Carcinoma, regional lymph nodes were divided into three compartments: (a) compartment 1 (lymph node station numbers 1-6); (b) compartment 2 (lymph node station numbers 7-12); and (c) compartment 3 (lymph node station numbers 14 and 16). Dendritic cells and MIB-1-positive immunocytes infiltrated compartment 1 lymph nodes in increased numbers compared with the lymph nodes of compartments 2 or 3 (P < 0.05). Conversely, intranodal NK cell infiltration did not differ significantly among the three compartments. The incidence of intranodal dendritic and MIB-1-positive cell infiltration in patients with submucosal gastric cancer was significantly higher than in patients with tumors that invaded beyond the muscularis propria. The decreased expression of these immunological markers correlated well with recurrent disease, regardless of tumor depth. The immunocyte level is higher in lymph nodes near the primary tumor (compartment 1) than in those that are distant from the tumor (compartments 2 and 3). This pertains to all three markers, i.e., NK, dendritic, and MIB-1-positive cells. Unlike dendritic and MIB-1-positive cells, intratumoral infiltration of NK cells did not correlate well with either lymph node compartment or the depth of tumor invasion. The degree of NK cell infiltration may be directly associated with antitumor effects, especially in compartment 1. A decrease in all three markers is associated with tumor recurrence.  (+info)

Growth regulated oncogene-alpha expression by murine squamous cell carcinoma promotes tumor growth, metastasis, leukocyte infiltration and angiogenesis by a host CXC receptor-2 dependent mechanism. (67/1358)

Growth Regulated Oncogene-alpha (GRO-alpha) is an autocrine growth factor in melanoma and is a member of the C-X-C family of chemokines which promote chemotaxis of granulocytes and endothelia through binding to CXC Receptor 2. We found previously that variants of murine squamous cell carcinoma PAM 212 which grow and metastasize more rapidly in vivo constitutively express increased levels of murine GRO-alpha, designated mGRO-alpha, or KC. We have examined the possible role of mGRO-alpha expression in malignant progression of squamous cell carcinoma PAM 212 in homologous BALB/c and BALB CXC Receptor-2 deficient mice. Transfection of the PAM 212 cell line which exhibits low expression of GRO-alpha and malignant potential with a pActin-KC vector encoding mGRO-alpha enabled isolation of PAM-KC expressing cell lines. These PAM-KC transfectants displayed an increased rate of growth and metastasis in BALB/c mice, similar to the highly malignant phenotype observed in spontaneously occurring metastatic variants. Furthermore, the PAM-KC tumors showed an increase in infiltration of host leukocytes and CD31+ blood vessels, consistent with increased CXC chemokine activity. The increased growth of PAM-KC cells was attenuated in CXCR-2 deficient mice, indicating that the increased growth was dependent in part upon host cells responsive to the CXC chemokine. Together, these results show that a CXC chemokine such as GRO-alpha can promote malignant growth of murine squamous cell carcinoma by a host CXCR-2 dependent pathway. Oncogene (2000) 19, 3477 - 3486  (+info)

Intra-tumoral cytolytic cells: pattern of distribution in B-cell non Hodgkin s lymphoma. (68/1358)

Non-Hodgkin s lymphomas (NHLs) constitute a heterogeneous group of lymphoid neoplasms and a majority of them in India are of B-cell phenotype. Varying numbers of T lymphocytes and natural killer (NK) cells are consistently present within the lymph nodes (LNs). The role of these reactive cells is becoming understood. TIA-1 is a cytotoxic granule associated RNA binding protein, the expression of which is restricted to cytotoxic T lymphocytes (CTLs) and NK cells. Snap frozen lymph node biopsies obtained from 41 B-cell NHLs were localized for intra-tumoral TIA-1 + cytolytic cells by immunohistochemistry. Distribution of T cell subsets and NK cells were also quantified. Cells expressing TIA-1 antigen was observed in all the cases, seen as a strong granular cytoplasmic signal. Results indicate significantly higher number of TIA-1 cytolytic cells outside (periphery of the follicle and interfollicular areas) than within the neoplastic follicle in follicular lymphomas (p<0.001). In small lymphocytic lymphomas, cytolytic cells were mainly seen as uniformly scattered single cells, distributed throughout the tumor environment. In mantle cell and diffuse large B-cell lymphomas these were most often seen as small clusters and less frequently as singly scattered cells. Higher numbers of CD4 + than the CD8 + T cells were observed in most cases. Contrary to the follicles in follicular hyperplasia, CD57 + NK cells were predominantly observed outside the neoplastic follicle in follicular lymphomas (FLs). These results outline specific interactions between the potential anti-tumoral cytolytic and the malignant cells of B-cell NHLs.  (+info)

Enhanced expression of IFN-gamma mRNA in CD4(+)or CD8(+)tumour-infiltrating lymphocytes compared to peripheral lymphocytes in patients with renal cell cancer. (69/1358)

The mRNA expression of the cytokines IFN-gamma, IL-10 and TNF-alpha and the proapoptotic factor Fas ligand (FasL) was compared in freshly isolated CD4(+)and CD8(+)tumour-infiltrating lymphocytes (TIL) and simultaneously obtained autologous CD4(+)and CD8(+)peripheral blood lymphocytes (PBL) from 20 patients with renal cell carcinomas (RCC). TIL were isolated from mechanically disaggregated tumour material and PBL from peripheral blood by gradient centrifugation. The cells of the interphase were depleted from tumour cells with anti-human epithelial antigen magnetic beads and then positive selection was performed with anti-CD4 or anti-CD8 magnetic beads. In these pure lymphocyte preparations the constitutive expression of cytokine and FasL mRNAs was determined by using a PCR-assisted mRNA amplification assay. In the CD4(+)TIL from the 20 patients with RCC, levels of mRNAs encoding for IFN-gamma (P+info)

Infiltration of CD8+ T cells in non-small cell lung cancer is associated with dedifferentiation of cancer cells, but not with prognosis. (70/1358)

CD8+ T cells infiltrating within cancer cell nests in human colorectal cancer were associated with a favorable patients' survival, suggesting the presence of anti-tumor immunity. The present study was designed to examine this concept in non-small cell lung cancer (NSCLC) by a retrospective analysis of 128 surgically resected cases. Immunohistochemical analysis showed that the number of CD8+ T cells within cancer cell nests in NSCLC was related to the histological subtype (large cell carcinoma or squamous cell carcinoma > adenocarcinoma) and the degree of dedifferentiation (undifferentiated type > differentiated type). In contrast to colorectal cancer, the number of CD8+ T cells in NSCLC had no statistically significant impact on the patients' survival. The present study demonstrated that the degree of infiltration of CD8+ T cells within cancer cell nests is dependent on the dedifferentiation of cancer cells in NSCLC, which could be one of the important aspects for the study of tumor immunity.  (+info)

Naturally occurring human lymphocyte antigen-A2 restricted CD8+ T-cell response to the cancer testis antigen NY-ESO-1 in melanoma patients. (71/1358)

Cancer testis (CT) antigens are particularly interesting candidates for cancer vaccines. However, T-cell reactivity to CT antigens has been detected only occasionally in cancer patients, even after vaccination. A new group of CT antigens has been recently identified using the SEREX technique based on immunoscreening of tumor cDNA expression libraries with autologous sera. We have used fluorescent HLA-A2/peptide tetramers containing an optimized antigenic peptide to directly identify HLA-A2-restricted CD8+ T cells specific for the SEREX-defined CT antigen NY-ESO-1 in melanoma patients. High frequencies of NY-ESO-1-specific CD8+ T cells were readily detected in peptide-stimulated peripheral blood mononuclear cells as well as in lymphocytes infiltrating melanoma lesions from patients with measurable antibody responses to NY-ESO-1. NY-ESO-1-specific CD8+ T cells were also detectable in peptide-stimulated peripheral blood mononuclear cells from some seronegative patients. Whereas the frequencies of NY-ESO-1-specific CD8+ T cells in circulating lymphocytes were usually below the limit of detection by tetramer staining, the presence of NY-ESO-1 CD8+ T cells displaying a memory phenotype was clearly detectable ex vivo in blood from a seropositive patient over an extended period of time. These results indicate that sustained CD8+ T-cell responses to CT antigens can naturally occur both locally and systemically in melanoma patients.  (+info)

Immunopathology of in situ seminoma. (72/1358)

In this study of the seminomatous human testis the composition, activity and apoptosis of lymphocytes infiltrating the immune-privileged seminiferous tubules with in situ seminoma were studied by immunohistochemistry and DNA fragmentation detection. Likewise the lymphocytes infiltrating the invasive seminomas were studied. The study showed equal numbers of CD4+ and CD8+ T cells and B cells, about 30% of the cells. Very few T gamma/delta and NK cells were present. The activity in terms of IL-2-R, FasL and perforin expression was low. Apoptosis of the lymphocytic cells was limited. No differences were observed between the lymphocytes in seminiferous tubules with in situ seminoma and the lymphocytes in invasive tumours. The study suggests that either specifically committed lymphocytes are not present or, if present, immune-suppressing mechanisms in addition to FasL may be working.  (+info)