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PubMed2004

The intensity of neutrophil infiltration controls the number of antigen-primed CD8 T cells recruited into cutaneous antigen challenge sites.

Recruitment of antigen-specific T cells into the skin is a critical initiating event during immune responses to many parasites and tumors as well as T cell-mediated, cutaneous, allergic responses and autoimmune diseases. Mechanisms directing T cell trafficking into skin remain largely undefined. Here, we show that cutaneous contact with reactive antigen induces KC/CXC chemokine ligand 1 production and neutrophil infiltration in an antigen, dose-dependent manner. The intensity of neutrophil infiltration into cutaneous antigen challenge sites, in turn, controls the number of antigen-primed T cells recruited into the site and the magnitude of the immune response elicited. The absence of responses in immune animals challenged with suboptimal doses of antigen is overcome by manipulating neutrophil infiltration that then directs antigen-primed T cell infiltration into the challenge site. This inflammation also directs T cells primed to one antigen (dinitrofluorobenzene) into the site when challenged with a completely different antigen (oxazolone). These results identify the intensity of neutrophil infiltration into cutaneous, antigen-deposition sites as a critical parameter for the level of antigen-primed T cell recruitment to mediate the adaptive immune response. This interplay between the innate and adaptive responses suggests a strategy to modulate, in a positive or negative manner, antigen-primed T cell infiltration into cutaneous inflammation sites.

Adaptation, Physiological↗

PubMed1996

T-cell infiltration of primary CNS lymphoma.

We stained 13 primary CNS lymphomas (PCNSLs) (six from patients with AIDS, seven from immunocompetent patients) with a panel of antibodies to T cells (pan T cell [CD3], T helper cell [CD4], T suppressor cell [CD8], delta/delta cell [CD4-8-]), B cells (CD20), hematopoietic cells (T200), and NK cell (CD56). We estimated the percentage of tumor cells staining with each antibody. All tumors were B-cell lymphomas. The non-AIDS tumors showed a significant infiltration with CD3+ cells (mean of 10.82% of total cells). The AIDS patients' tumors showed a smaller percentage of CD3+ infiltrating cells (mean, 4.88% of total cells) (p<0.01). CD4+ cells were 9.11% of the total hematopoietic cells in the non-AIDS patients and 3.13% in AIDS patients (p<0.01). AIDS patients showed some CD8+ cells (0.3%), which was significantly higher than in immunocompetent patients (0%) (p<0.05). Very few tumor cells stained with the NK cell and delta/delta cell markers. Both immunocompetent and AIDS patients with PCNSL exhibit significant CD3+ and CD4+ cell infiltration of their tumors; this infiltration is significantly lower in AIDS patients. AIDS patients show a minor CD8+ cell infiltration of their tumors. These results on PCNSL are different from systemic lymphomas, which show a higher CD4 and CD8 cell infiltration, and may offer insights into the more aggressive nature of AIDS-related PCNSL.

Antigens, CD↗

PubMed1993

T-cell receptor V-gene usage in neoplasms of the central nervous system. A comparative analysis in cultured tumor infiltrating and peripheral blood T cells.

The use of tumor-infiltrating lymphocytes in the treatment of central nervous system (CNS) neoplasms has met with serious obstacles due to difficulty of culture and poor characterization. Since in other tumors the therapeutic effects of tumor-infiltrating lymphocytes have been shown to rely on T-cell receptor engagement, the authors addressed the question as to whether expression of T-cell receptor variable (V) domains in cultured tumor-infiltrating lymphocytes from CNS is different from that of autologous cultured peripheral blood mononuclear cells. Infiltrating lymphocytes from CNS neoplasms, including primary malignancies, metastatic cancers, and meningiomas, were cultured in the presence of interleukin-2 and anti-CD3 monoclonal antibodies (MoAb's) in order to obtain optimum growth of T cells. Autologous peripheral blood mononuclear cells from the same patients were similarly cultured. After 4 to 5 weeks of culture, 97.3% +/- 2.6% (mean +/- standard deviation) of the resulting cell populations were CD3-positive lymphocytes. The expression of T-cell receptor V domains was then studied by using a panel of 12 MoAb recognizing gene products from T-cell receptor V-alpha 2, V-beta 5, 6, 8, and 12, V-gamma 4 and 9 families, and from two subfamilies of V-delta 2. Remarkably, in over 70% of all paired measurements, percentages of T cells expressing discrete T-cell receptor V-gene products were found to be virtually identical in tumor- and peripheral blood-derived cultured cell populations, with differences never exceeding 1%. In contrast, a different expression of individual V-gene products, concerning both alpha/beta and gamma/delta T-cell receptors, could be detected between cultured tumor-infiltrating lymphocytes and autologous peripheral blood-derived T lymphocytes in seven of 12 patients. In two cases, significant differences between the two populations were also observed in the proliferative responses obtained upon stimulation with staphylococcal enterotoxins that trigger defined V-beta T-cell receptors. Altogether, these data suggest that the T-cell receptor repertoire of cultured tumor-infiltrating lymphocytes from CNS tumors, suitable for use in adoptive immunotherapies, differs from that of autologous cultured peripheral blood mononuclear cells.

Adult↗

PubMed2002

Translocation of an intracellular antigen to the surface of medullary breast cancer cells early in apoptosis allows for an antigen-driven antibody response elicited by tumor-infiltrating B cells.

Tumor-infiltrating lymphoplasmacytic cells are a key feature of medullary carcinoma of the breast (MCB), a distinct subtype of human breast cancer that, despite cytologically anaplastic characteristics, has a more favorable prognosis than other types of breast cancer. Since it has been proposed that the improved clinical outcome is due at least in part to the presence of a prominent lymphoplasmacytic cell infiltrate in the tumor stroma, we recently examined the tumor-infiltrating B cell response in MCB and showed that it is oligoclonal and directed against an intracellular protein translocated to the cell surface upon MCB cell apoptosis. Human Abs cloned from MCB lymphoplasmacytic infiltrate-derived phage display libraries and reflecting the dominant part of the response were used to identify the target Ag as actin. Here, we have characterized in detail the cloned human IgG Abs and the translocation process of actin to the cell surface of apoptotic MCB cells. Our analysis shows that the cloned Abs bind specifically and with high affinity to actin, as determined by ELISA and surface plasmon resonance. Sequence analysis revealed that the Abs are highly somatically mutated, with high replacement to silent ratios, indicative of an Ag-driven, affinity-matured response. Interestingly, the tumor-infiltrating B cells in half the MCB patients mainly exhibited an IgG2 response, while IgG1 dominated in the others. To gain insight to the molecular events that may elicit such an Ab response, we examined the translocation of actin to the cell surface of apoptotic MCB cells using flow cytometry and laser scanning cytometry. Our results show that actin becomes exposed on the cell surface of a large proportion of apoptotic MCB cells as an early apoptotic event. We propose that the Ab response against actin produced by tumor-infiltrating B lymphoplasmacytic cells is Ag-driven, affinity-matured, and elicited due to the increased rate of apoptosis occurring within the MCB tumor that facilitates the translocation and proteolytic fragmentation of intracellular proteins.

Actins↗

PubMed2000

Intranodal antitumor immunocyte infiltration in node-negative gastric cancers.

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.

Adult↗

PubMed2001

Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas.

The purpose of this study was to explore whether there is a linkage between the infiltration of CD8(+) T cells and the risk of death from esophageal cancer. Cases of 70 consecutive patients in whom esophageal squamous cell carcinomas ( n = 33) or adenocarcinomas (n = 37) were R0-resected between 1993 and 1999 were reviewed. The presence of activated CD8(+) T cells was evaluated by quantitative real-time PCR and immunohistochemistry and compared to clinical and pathological stages. The primary end point analyzed was overall survival, and a multivariate analysis was performed to distinguish any factors conferring an improved survivorship. Intratumoral (i.t.) CD8(+) T cells accumulating within the epithelial complexes were detected in 11 of all (16%) cases: in 9 of 25 (36%) patients with Union Internationale Contrele Cancer stage I or II versus 2 of 45 (4%) patients with Union Internationale Contrele Cancer stage III or IV (P = 0.001). Intratumoral CD8(+) T cell infiltrations showed proliferative activity and also IFN-gamma secretion. The presence of i.t. CD8(+) T cell infiltration more than peritumoral infiltration was associated with a good prognosis in both squamous cell and adenocarcinomas. Multivariate analysis showed that i.t. CD8(+) T cell infiltration was an independent prognostic factor (hazard ratio, 0.5; P = 0.0004) indicating favorable outcome. In conclusion, the presence of CD8(+) T cell infiltration in esophageal carcinomas is a favorable prognostic factor that should have diagnostic and therapeutic implications.

Adenocarcinoma↗

PubMedDate not supplied

Preoperative IL-2 immunotherapy enhances tumor infiltrating lymphocytes (TILs) in gastric cancer patients.

BACKGROUND/AIMS: Tumor infiltrating lymphocytes (TILs), recognized as a tumor-host reaction, have been linked to prognosis in various tumors, with a clear positive correlation between the density of the lymphoid infiltrate at the advancing margin of the tumor and the prognosis of the patients. TILs are somewhat activated by tumor associated antigens and by IL-2 endogenous release. The aim of this study is to verify if subcutaneously administered IL-2 is able to enhance TILs in gastric cancer patients and is able to influence the prognosis of the patients. METHODOLOGY: We enrolled 39 consecutive patients with gastric adenocarcinoma. Patients were randomized to be treated with surgery alone (control group, 20 patients) or with surgery plus preoperative IL-2 (Interleukin-2) administration (treated group, 19 patients). Total lymphocytes, CD4 and CD4/CD8 were evaluated pre- and postoperatively. Peritumoral stromal reaction, neutrophils, lymphocytes and eosinophils infiltration in tumor histology were evaluated as well as survival curves and compared between the groups. RESULTS: IL-2 treatment was safe and well tolerated, and in the IL-2 treated group a significant increase over the baseline pretreatment values of the total lymphocyte, CD4 and CD4/CD8 on both the 14th and 50th postoperative days was observed (p < 0.05). Peritumoral stromal reaction, neutrophils and eosinophils infiltration did not shown any statistical difference between the two groups. Otherwise we observed a statistically significant difference in the peri- and intratumoral lymphocytes infiltration between IL-2 treated and control patients (p = 0.000026). Median overall and disease-free survivals were longer, even if not significantly, in the IL-2 group than in the control arm (p = 0.089 and p = 0.09 respectively). CONCLUSIONS: Our data shows that IL-2 seems to be able to induce substantial changes in the inflammatory infiltration of the neoplasm, improving the host activity toward the tumor and enhancing the TILs phenomenon in gastric cancer patients. This feature seems to improve the prognosis of the patients.

Adenocarcinoma↗

PubMed1994

Regulation of testicular infiltration in acute lymphoblastic leukaemia of the rat.

The testis is a common site of relapse in childhood acute lymphoblastic leukaemia (ALL). In adults, testicular relapses of ALL are very rare. A similar age-difference in the frequency of the testicular infiltration exists also in the rat T-cell leukaemia. In the present investigation, the effect of various hormonal treatments and unilateral cryptorchidism on the form of testicular infiltrates by the rat T-cell leukaemia was studied. Inhibition of testicular activity by estradiol treatment (E2) of early pubertal rats injected i.p. with rat T-leukaemic lymphoblasts significantly decreased the proportion of the testis occupied by leukaemic infiltrates. The proportion of the testis occupied by leukaemic infiltrates was significantly higher in the abdominal testes of both early and late pubertal unilaterally cryptorchid rats, than in the scrotal testes of leukaemic control rats. Daily treatment of early pubertal rats with human chorionic gonadotrophin (hCG), or human menopausal gonadotrophin (hMG), did not have an effect on testicular leukaemic infiltration. These studies demonstrate that the leukaemic infiltration of the testis is influenced by the changes in the physiological activity of the testes.

Animals↗

PubMed1996

Lymphomatous infiltrates within leptomeninges and spinal roots in adult patients with non-Hodgkin's lymphomas after intrathecal methotrexate administration.

Based on post-mortem neuropathological evaluation the authors analyzed the incidence and distribution of the lymphomatous infiltrates within the leptomeninges and spinal roots in 21 patients with high grade non-Hodgkin's lymphomas (HGNHL) treated with intrathecal methotrexate (ITMTX) prophylaxis. The investigations revealed that lymphomatous infiltrates were most frequent within cerebellar leptomeninges and around spinal roots. In spinal leptomeninges and roots the infiltrates occurred significantly rare after more than 3 ITMTX injections, but further ITMTX applications did not diminish infiltrates incidence in the mentioned regions. In the remaining regions infiltrates incidence was similar, irrespective of the number of ITMTX injections. From the neuropathological point of view ITMTX prophylaxis isn't able to prevent the development of the infiltrates in the mentioned regions. In an attempt to determine the clinical usefulness of the ITMTX prophylaxis in adult patients with HGNHL and to elaborate optimal prophylactic management, the more detailed clinical and pathological evaluations are required.

Adolescent↗

PubMed1996

[Prognostic significance of histopathological findings (including lymphocyte infiltration) in renal cell carcinoma].

We compared the prognosis with the histopathological findings including intravenous invasion and lymphocytic infiltration inside or adjacent to the primary tumor in 50 renal cell carcinoma patients who underwent radical nephrectomy. We compared the primary tumor to intravenous invasion or metastases in histopathological findings. One-, three- and five-year survival rates for all patients were 91.7, 71.5 and 60.7%, respectively. Significant prognostic factors were tumor size, growth pattern, invasion of fat tissue into peripheral kidneys lymph nodes, distant metastases, intravenous invasion and tumor grade, especially lymph nodes and distant metastases (P < 0.001). Degree of lymphocytic infiltration inside or adjacent to primary tumor was divided into three groups. Five-year survival rates were 86.2% of the patients (n = 15) with apparent lymphocytic infiltration and 48.8% of the patients (n = 18) had few infiltrated lymphocytes. The patients with apparent lymphocytic infiltration showed a trend of better prognosis compared to the patients with few infiltrated lymphocytes (P < 0.1). Tumor grade was higher in 3 of the 28 patients with intravenous invasion and 6 of the 9 patients with distant metastases than in those with primary tumors. However, there was no significant correlation between prognosis and malignant potential of intravenous invasion or distant metastases.

Adult↗

PubMed1981

Rabbit model of phlyctenulosis and catarrhal infiltrates.

Phlyctenules and catarrhal infiltrates of the human cornea have been described in association with staphylococcal blepharitis. Rabbits immunized and boosted with phenol-inactivated Staphylococcus aureus had a fourfold or greater increase in antibody titer to S aureus and delayed hypersensitivity to S aureus. After topical challenge with viable S aureus, the rabbits in this model had vascularized, elevated, nodular infiltrates of the cornea resembling phylctenules in humans and peripheral corneal infiltrates running parallel to the limbus and separated from it by a lucid interval resembling catarrhal infiltrates in humans. The nodular corneal infiltrates were found in a subepithelial location and were composed of vessels, polymorphonuclear leukocytes and mononuclear cells, including lymphocytes, plasma cells, and macrophages. The peripheral corneal infiltrates separated from the limbus by a lucid interval were found in the anterior stroma beneath the corneal epithelium and were composed of polymorphonuclear leukocytes and mononuclear cells.

Animals↗

PubMed1996

Restricted usage of T-cell receptor V alpha genes in infiltrating cells in murine hearts with acute myocarditis caused by coxsackie virus B3.

In murine myocarditis, it has been shown that natural killer cells first infiltrate the heart, followed by activated T-cells, which play an important role in the pathogenesis of the myocardial damage. In the same model of acute myocarditis, the repertoire of T-cell receptor (TCR) V beta genes in infiltrating cells in the heart has also been shown to be restricted. To study the nature of T-cell infiltration in more detail, the expression of TCR V alpha genes in infiltrating cells in the heart has been analysed by the polymerase chain reaction (PCR), confirmed by Southern blot hybridization with a C alpha cDNA probe. In contrast to spleen lymphocytes, the repertoire of V alpha gene transcripts in the heart was restricted. Infiltrating cells expressing V alpha 10 were found in five of eight hearts of mice with acute myocarditis and infiltrating cells expressing V alpha 7 and V alpha 3 were found in two of eight and one of eight hearts, respectively. Restricted TCR V alpha as well as V beta repertoires indicate that a specific antigen, in the heart was targeted, presented at the groove of major histocompatibility complex molecules. These findings raise the possibility of specific immunotherapy with synthetic TCR V alpha or V beta peptides to prevent T-cell-mediated myocardial damage in patients with viral myocarditis.

Animals↗

PubMed1999

L-selectin and its ligands mediate infiltration of mononuclear cells into kidney interstitium after ureteric obstruction.

It was previously reported that the L-selectin ligands detected by a rat L-selectin and human IgG chimeric molecule (rLEC-IgG) are expressed in the distal tubules of the kidney, where no leukocyte traffic is seen under physiological conditions. In the present study, the role of L-selectin ligands in leukocyte infiltration into the kidney interstitium was investigated using a rat ureteric obstruction model. After ligation of the ureter, ligands for L-selectin rapidly disappeared from tubular epithelial cells and were relocated to the interstitium and peritubular capillary walls, where infiltration of monocytes and CD8(+) T cells subsequently occurred. Mononuclear cell infiltration was significantly inhibited by intravenous injection of a neutralizing monoclonal antibody (MAb) against L-selectin, indicating the possible involvement of an L-selectin-mediated pathway. Interestingly, immunohistochemical studies with a MAb against sulphatide showed that the distribution of sulphatide, known to be one of the candidates of L-selectin ligand, was almost indistinguishable from the staining pattern of rLEC-IgG in both normal and ureteric obstructed kidneys, suggesting that sulphatide and/or related molecule(s) relocated to the renal interstitium were recognized by leukocyte L-selectin, leading to interstitial leukocyte infiltration. In line with this notion, intravenous injection of sulphatide markedly inhibited leukocyte infiltration, suggesting that L-selectin-sulphatide interaction may play a pivotal role in interstitial leukocyte infiltration in the kidney following ureteric obstruction.

Animals↗

PubMed1998

Eosinophil infiltration and degranulation in normal human tissue.

Localization of eosinophil granule major basic protein by immunofluorescence permits recognition of both eosinophil infiltration and degranulation. Over the past decade and a half, our laboratory has shown that eosinophil infiltration and degranulation occur in many diseased tissues in humans; among normal tissues studied as controls, only the gut showed striking eosinophil infiltration and degranulation. Using an indirect immunofluorescence procedure for the detection of major basic protein, we extended our analyses of normal human tissues to include tissues from essentially all body organs; a total of 117 biopsy/autopsy specimens were analyzed. To determine whether the method of tissue procurement affected the level of eosinophil degranulation in the normal gastrointestinal tract, normal proximal jejunum from six patients was biopsied using either an endoscopic forceps or a scalpel at the time of elective surgery and examined by immunofluorescence. Spleen, lymph node, and thymus tissues showed eosinophil infiltration with scant evidence of degranulation, but the only organ showing both eosinophil infiltration and remarkable degranulation was the gastrointestinal tract. Eosinophil degranulation was significantly increased in specimens obtained by endoscopic forceps compared to those obtained by scalpel (P = 0.021). These results indicate that tissue procurement methods affect the degree of eosinophil degranulation in the gut. Thus, among normal human body organs, both eosinophil infiltration and appreciable degranulation consistently occur only in the gut.

Adult↗

PubMed1984

Immunohistologic detection of lymphocyte subpopulations infiltrating in human oral cancer with special reference to its clinical significance.

Cancer tissues from 30 patients with squamous cell carcinoma of the oral cavity were examined immunohistopathologically as to the responsiveness of the host against its own cancer cells in both biopsy and surgically resected specimens from the same patients. Subpopulations of the infiltrating lymphocytes in cancer tissues were identified on paraffin-embedded serial sections by a modified indirect immunoperoxidase technique (PAB method) in which it was combined with peroxidase-antiperoxidase (PAP) complex and avidin-biotin system with rabbit anti-human B-cell, peripheral T-cell sera. Macrophages were also identified by nonspecific acid esterase staining. T-cells were predominant over B-cells in 26 of 30 tissues in biopsy specimens and 23 of 30 in surgically resected specimens with bleomycin treatment. T-cell infiltration in the peripheral region of the tumor was more prominent than that in the stroma among the cancer nests. T-cells surrounded the cancer nests, occasionally accumulated around the cancer cells, infiltrated at the marginal part of the cancer nests, and frequently produced perivascular massive accumulations. B-cells and macrophages, on the other hand, were almost absent or negligible around cancer tissues. The grade of T-cell infiltration, especially in biopsied specimens, was correlated well to the size of the tumor, and also more marked significantly in patients without cervical lymph node metastasis than in those with lymph node metastasis. Furthermore, there was a significant correlation between the grade of T-cell infiltration at the peripheral region of the invading cancer mass in initial biopsy specimens and the clinical tumor regression rates with bleomycin treatment, but it did not correlate to the surgically resected specimens. These facts suggest that T-cells might inhibit the development and spreading of the cancer cells, and that the T-cell infiltration correlates with the clinical course or prognosis of the oral cancer patients.

Adult↗

PubMed1987

Characterization and frequency distribution of lymphoreticular infiltrates in axillary lymph node metastases of invasive ductal carcinoma of the breast.

One hundred and seventy-five axillary lymph nodes containing metastatic deposits from 46 invasive ductal carcinomas of the breast were evaluated histologically and immunohistologically. The study yielded the following results: (1) tumor-infiltrating lymphoreticular cells preferentially accumulated in the stromal bands; the tumor foci generally showed a considerably lower degree of infiltration; (2) in most cases, monocytes/macrophages (Mono 1+) represented the overwhelming majority of tumor-infiltrating cells; (3) next in frequency were T-lymphocytes (Leu-1+), especially CD4+ lymphocytes (Leu-3a+), while CD8+ lymphocytes (Leu-2a+) mostly occurred only in moderate numbers; (4) B-lymphocytes (To15+), plasma cells, natural killer cells (Leu-7+), tissue mast cells, and T-accessory reticulum cells (OKT 6+) were observed mostly in low or very low numbers, while eosinophils were nearly absent and B-accessory reticulum cells (Ki-M4+) were totally absent from the lymphoreticular infiltrates. Definite conclusions regarding the functional properties of the tumor-infiltrating cells cannot be drawn from an immunohistologic analysis in situ alone, but the preferred localization of most tumor-infiltrating cells in the stroma does not support an intensive interaction between the host defenses and the metastatic tumor.

Antigen-Presenting Cells↗

PubMed1995

T lymphocytes infiltrating advanced grades of cervical neoplasia. CD8-positive cells are recruited to invasion.

BACKGROUND: Impaired cellular immunity appears to be a risk factor for progression of cervical neoplasia, but the immunobiology of neoplastic progression is poorly understood. The objective of this study was to characterize the subpopulations of T lymphocytes that infiltrate various grades of cervical neoplasia including metaplasia to invasive cancer in immunocompetent women. METHOD: In 65 patients with a spectrum of cervical disease ranging from normal cytology to carcinoma, the relative proportions of total T lymphocytes and CD4- or CD8-expressing (helper or cytotoxic) T lymphocyte subsets were determined by immunohistochemistry. RESULTS: When the invasive carcinoma stromal infiltrate was compared with the infiltrate of preinvasive lesions, the numbers of total T cells and the CD8-positive subset increased significantly in the invasive cancers (P < 0.005). Although immunocyte infiltrates were highly concentrated in focal clusters beneath the preinvasive squamous lesions, the CD8-positive immunocytes diffusely infiltrated the invading tumor. CONCLUSIONS: The CD8-positive T cell infiltrate far exceeded the CD4-positive cells in the invasive, but not in the preinvasive lesions, a finding that suggests that CD8 cells are recruited preferentially to cervical lesions with progression to invasion.

CD4-Positive T-Lymphocytes↗

PubMed2000

Targeting angiogenesis inhibits tumor infiltration and expression of the pro-invasive protein SPARC.

The solid growth of high-grade glioma appears to be critically dependent on tumor angiogenesis. It remains unknown, however, whether the diffuse infiltration of glioma cells into healthy adjacent tissue is also dependent on the formation of new tumor vessels. Here, we analyze the relationship between tumor angiogenesis and tumor cell infiltration in an experimental glioma model. C6 cells were implanted into the dorsal skinfold chamber of nude mice, and tumor angiogenesis was monitored by intravital fluorescence videomicroscopy. Glioma infiltration was assessed by the extent of tumor cell invasion into the adjacent chamber tissue and by expression of SPARC, a cellular marker of glioma invasiveness. To test the hypothesis that glioma angiogenesis and glioma infiltration are codependent, we assessed tumor infiltration in both the presence and the absence of the angiogenesis inhibitor SU5416. SU5416 is a selective inhibitor of the VEGF/Flk-1 signal-transduction pathway, a critical pathway implicated in angiogenesis. Control tumors demonstrated both high angiogenic activity and tumor cell invasion accompanied by strong expression of SPARC in invading tumor cells at the tumor-host tissue border. SU5416-treated tumors demonstrated reduced vascular density and vascular surface in the tumor periphery accompanied by marked inhibition of glioma invasion and decreased SPARC expression. A direct effect of SU5416 on glioma cell motility and invasiveness was excluded by in vitro migration and invasion assays. These results suggest a crucial role for glioma-induced angiogenesis as a prerequisite for diffuse tumor invasion and a possible therapeutic role for anti-angiogenic compounds as inhibitors of both solid and diffuse infiltrative tumor growth.

Angiogenesis Inhibitors↗