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PubMed1990

Methylcholanthrene-induced tumors in adult and in aging rats: infiltrating cells and their ADCC activity.

In our previous studies we found that the slower growth of syngeneic, immunogenic MC-induced sarcoma (MC-Sa) in aging rats was followed by the higher activity of spleen lymphocytes in ADCC assay. The purpose of the present paper was to study infiltrating cells of immunogenic and non-immunogenic MC-Sa and to estimate in situ ADCC activity in relation to the growth of MC-Sa transplants in adult and aging rats. It was found that MC-Sa's were infiltrated mainly by lymphocytes. Among cells infiltrating tumor the high percentage of cells with Fc receptor was present. During progressive tumor growth the percentage of infiltrating cells and also FcR+ cells significantly decreased within immunogenic MC-Sa, but did not change in the case of the non-immunogenic MC-Sa. In cell infiltrates of both tumors no differences between adult and aging rats were observed. At early stages of the tumor growth the cells active in ADCC assay were present within both MC-Sa. The slower growth of immunogenic MC-Sa in aging rats compared with adults was connected with longer maintenance of ADCC activity in situ. In the case of non-immunogenic MC-Sa, which grew at similar rate in both groups of rats, no differences in ADCC activity between adult and aging animals were observed. It is suggested that in situ ADCC activity may be one of the mechanisms responsible for the slower growth of immunogenic MC-Sa in aging rats.

Aging↗
PubMed1990

[Treatment of adult T-cell leukemia with intravenous administration of IFN-gamma-immunohistochemical studies of infiltrating cells in cutaneous lesions].

Three cases of adult T-cell leukemia (ATL) with cutaneous lesions of disseminated papules or nodules were treated with recombinant human interferon-gamma (IFN-gamma) by intravenous administration. Clinical stage of each case was different, i.e., 1) preleukemic state of ATL (pre-ATL), 2) chronic-type ATL, and 3) crisis-type ATL. We evaluated clinical efficacy of IFN-gamma, and performed immunohistochemical analysis of biopsy specimens derived from cutaneous lesions of the patients both before and during treatment. The case of pre-ATL achieved a complete remission of cutaneous lesions for 18 months. The other cases also obtained clinical responses with a shorter duration, but relapsed while they are still on IFN-gamma therapy. The cutaneous lesions reduced in size during the therapy associated with a decrease in the ratio of Leu3a + 3b (CD4)+ cells in all three cases. After the therapy, Leu7 (HNK-1)+ cells increased in all cases, and LeuM5 (CD11)+ cells did in two. These results suggested that IFN-gamma enhanced tumor immunity although its clinical effect was less clear. Only in the cutaneous lesions of pre-ATL case an increased number of LeuM5+ cells, probably monocyte-macrophage series in host defence, were seen before the therapy. And IFN-gamma was useful for this case after all.

Female↗
PubMed1990

[Infiltrative and cytolytic activities of lymphokine-activated killer (LAK) cells against a human glioma mass: ultrastructural analysis using a three-dimensional multicellular spheroid model].

In the present study, we have investigated not only the infiltrative and cytotoxic activities of lymphokine-activated killer (LAK) cells on a tumor mass, but also the ultrastructural cell-to-cell interaction between LAK effector cells and target tumor cells during the cytolytic process within a three-dimensional solid tumor. A multicellular tumor spheroid (MTS) of a human malignant glioma cell line (U-251MG) was utilized as a solid tumor model. LAK cells were generated from peripheral blood lymphocytes (PBL) of a healthy donor after 4-day culture in the presence of interleukin-2 (IL-2). MTSs of 500 microns diameter were cocultivated with either LAK cells or non-activated PBL, and then time-sequential kinetic, morphological, and ultrastructural examinations were carried out. It was demonstrated that the number of viable tumor cells present within MTSs gradually decreased in parallel with the increase in the number of LAK cells. Morphological analyses revealed that LAK cells directly infiltrated toward the inner areas of MTSs and caused a progressive tumor destruction. In contrast, PBL hardly exhibited such activities. Ultrastructurally, it was found that the infiltrating LAK effector cells were composed of heterogeneous subpopulations, T-like cells and large granular lymphocyte (LGL)-like cells, and that both types of lymphocytes tightly adhered to the tumor cells and extended their cytoplasmic extensions deeply into the targets which underwent a progressive degeneration. Concerning the cellular interaction, it was found that these two kinds of LAK cells displayed some distinct ultrastructural feature in the process of target cell killing. Particularly, it should be stressed that LGL-like LAK cells exhibited a significant development of the intracytoplasmic secretory granules, suggesting an association with the lethal hit of target cell lysis.

Brain Neoplasms↗
PubMedDate not supplied

[Oral manifestations of acute leukemia].

The oral manifestation of leukemias is in some cases, the first clinical sign of the disease, being its recognition by the Dentist of capital importance to the adequate orientation of patient. In this manifestation had been shown, and the function of Dentist in the control and maintenance of oral health of leukemic patients in treatment had been emphasized.

Antineoplastic Agents↗
PubMed1991

New biologic markers in non-Hodgkin's lymphomas.

Many of the tumor markers mentioned in this article may seem to be of only research or theoretic interest. However, many of those mentioned are likely to be of great clinical utility in the future. In particular, the strength of these immunohistochemical findings have been compared with standard clinical prognostic features (e.g., stage, age, B symptoms) and have been modeled to show independent prognostic relevance in both intermediate-grade and low-grade lymphomas. Beyond their predictive value, these markers have identified phenotypes that may serve as new therapeutic targets: (1) restoration of HLA loss with alpha and gamma interferons; and (2) restoration of tumor-infiltrating T-cell lymphocytes with interleukin-2. New phenotype-directed cytokine therapies seem compelling with this new knowledge. We await future prospective trials of phenotyping to further refine this new exciting prospect.

Antibodies, Monoclonal↗
PubMed1992

Engraftment of human peripheral blood leukocytes into severe combined immunodeficient mice results in the long term and dynamic production of human xenoreactive antibodies.

Severe combined immunodeficient (SCID) mice engrafted with human peripheral blood leukocytes (hu-PBL-SCID) represent a potentially important small animal model for the study of human immune function. Attempts to generate human primary immune responses to exogenous Ag in the hu-PBL-SCID have had limited success which raises questions about the functional capacity of human lymphocytes in the SCID environment. Here, we demonstrate that the spontaneously secreted human Ig in hu-PBL-SCID includes antibodies with specificity for several different mouse RBC (mRBC) proteins. These antibodies apparently reflect the transfer of peripheral B cells which are responsible for the production of naturally occurring xenoreactive antibodies in the donor. Western blot analysis showed that engraftment of anti-mRBC specificities was random among mice receiving PBL from the same donor sample. In at least one mouse, this engraftment was polyclonal and included human IgM and IgG which recognized at least 12 different mRBC proteins ranging in size from 35 to > 200 kDa. Anti-mRBC specificities were found to vary with time demonstrating a dynamic expression of the human xenoreactive repertoire in hu-PBL-SCID. In contrast to mice engrafted with human PBL, mice engrafted with another source of human B cells, i.e., tumor-infiltrating leukocytes, produced very little or no human anti-mRBC antibody. Ag-driven proliferation of xenoreactive clones may result in a skewing of the engrafted human B cells in hu-PBL-SCID which could account in part for the limited ability of hu-PBL-SCID to respond to exogenous Ag. The long term production of anti-mRBC antibodies and the modulation of the expressed xenoreactive repertoire observed in hu-PBL-SCID represents an opportunity to study the molecular genetics and cell biology of the human humoral immune response to a defined complex Ag.

Adsorption↗
PubMed1991

Special subtypes of pulmonary adenocarcinomas indicated by different tumor cell HLA-expression and stromal infiltrates. A light, electron microscopic and immunohistologic study.

A total of 31 human peripheral adenocarcinomas (AC) of the lung were subclassified by light and electron microscopy according to their phenotypic characteristics. The expression of HLA-A,B,C and HLA-DR on tumor cells, and the degree of subclassified mononuclear cell infiltration were determined using immunohistologic and morphometric methods. The study shows that pulmonary AC can be subdivided in two main types with different properties. The first type is characterized by mucin production comparable to that of bronchial goblet cells. These mucinous AC of type I show nearly no expression of HLA-DR; the tumor volume fraction with HLA-A,B,C expression is greatest in highly differentiated AC I, and decreases significantly with lower grades of differentiation. The AC of type II, possibly originating from the bronchioloalveolar transitional zone, show properties of Clara cells and of type II-pneumocytes by light and electron microscopy. These features include apically located electron-dense granules and lamellar bodies occurring often simultaneously. Both groups of HLA-antigens, HLA-A,B,C and HLA-DR, are homogeneously distributed in a similar phenotypic fashion to Clara cells and pneumocytes II of the normal lung. The significant differences in mononuclear cell infiltration between the two tumor types are possibly induced by the different HLA-DR expression, which have not been seen in AC from other sites. In AC II with homogeneous HLA-DR expression in the tumor epithelium, the numbers of tumor-infiltrating Langerhans cells, and T- and B-lymphocytes are significantly higher than in AC I, possibly indicating better host immunologic defense mechanisms against these tumors.

Adenocarcinoma↗
PubMed1991

Antitumor effector mechanism of interleukin-1 beta at a distant site in the double grafted tumor system.

Recombinant human interleukin-1 beta (IL-1 beta) inhibited the growth of not only the right, but also the left non-treated tumor in a double grafted tumor system. Since the antitumor activity of IL-1 beta against the right and left tumors was not seen in nude mice, lymphocytes have a key role in the antitumor effect of intratumoral administration of IL-1 beta. TIL (tumor-infiltrating leukocytes) obtained from left and right side tumors treated with IL-1 beta were examined by Winn assay for their antitumor activity against Meth-A sarcoma in BALB/c mice. TIL from the right side clearly inhibited the growth of admixed Meth-A cells, but control TIL did not. Spleen cells and right and left regional lymph node cells prepared from IL-1-treated mice were examined for Lyt-1, Lyt-2 and L3T4 phenotypes. The number of Lyt-1-positive lymphocytes increased in the spleen and in the right regional lymph nodes after intratumoral administration of IL-1. Isolated tumor cells obtained from the right tumor treated with IL-1 beta and the left side tumor on day 6 were cultured in RPMI 1640 with 10% fetal calf serum for 24 h. The culture supernatants were harvested and tested for the presence of chemotactic activity for neutrophils or macrophages. Significant neutrophil chemotactic factor and macrophage chemotactic factor activities were detected in the culture media from IL-1-treated tumor tissues cultured for 24 h. Neither significant neutrophil nor macrophage chemotactic activity was detected in the media from untreated tumor tissues. These results suggest that intratumoral administration of IL-1 first induces neutrophils and macrophages in the right tumor, then Lyt-1-positive cells in the right regional lymph nodes and in the spleen, and subsequently induces macrophages in the left, non-treated tumor.

Animals↗
PubMed2026

MIF-CD74 axis facilitates MDSC infiltration in the tumor microenvironment of pancreatic ductal adenocarcinoma.

Immune checkpoint inhibitors show insufficient efficacy against pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment (TME) has a remarkable influence on responsiveness to cancer immunotherapy. The aim of this study was to investigate immunosuppressive characteristics of TME in PDAC tissues. The flow cytometry (FCM) of PDAC surgical specimens revealed that the profile of tumor-infiltrating leukocytes was classified into myeloid cell- and T-cell-dominant subtypes; the myeloid subtype was associated with poorer patient outcomes. Myeloid-derived suppressor cells (MDSCs) showed the highest hazard ratio among various myeloid cell types. Single-cell RNA sequencing and FCM revealed that most MDSCs, but not lymphocytes, in PDAC tissues characteristically express CD74. Macrophage migration inhibitory factor (MIF), a CD74 ligand, was highly expressed in cancer-associated fibroblasts (CAFs) and cancer cells. Spatial transcriptomics demonstrated that the MIF-CD74+ myeloid cell interaction was recognized in CAF-dominant areas in PDAC tissue. CAFs expressing immune suppressor molecules such as MFAP5 and LRRC15 were consistent with MIF+ CAFs. Furthermore, MIF+ CAFs enhanced the migratory activity of MDSCs and promoted MDSC induction and activation. In the murine model, MDSCs were significantly increased in MIF-expressing PDAC tumors, as were CD74+ M-MDSCs per M-MDSC, confirming in vivo interaction between CD74 and MIF. MDSCs play a crucial role in creating an immunosuppressive TME in PDAC; the MIF-CD74 axis drives interactions between MDSCs and CAFs.

Humans↗
PubMed2026

In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell antitumor immunity.

T cell dysfunction critically limits the efficacy of T cell-based immunotherapies in solid tumors, yet the intrinsic regulators of T cell dysfunction remain incompletely understood. Through an in vivo genome-wide CRISPR screen in tumor-infiltrating CD8+ T cells, we identified Forkhead Box R1 (FOXR1) as a potent transcriptional suppressor of CD8+ T cell effector functions. Genetic ablation of FOXR1 significantly enhanced cytokine production and cytotoxic capacity in both murine and human CD8+ T cells, whereas its overexpression impaired T cell activation and effector molecule expression. Mechanistically, multiomics integration of RNA-seq, CUT&Tag-seq, and ATAC-seq revealed that FOXR1 binds directly to promoter regions of key effector genes, including IL2, GZMB, and PRF1, and represses their expression. Importantly, FOXR1 deletion in human anti-CD19 CAR T cells improved their efficacy against solid tumors, demonstrating that FOXR1 is a checkpoint of T cell effector function and targeting FOXR1 is a promising strategy to enhance CAR T cell efficacy against solid tumors.

Animals↗
PubMed1991

Functional evaluation of tumor-infiltrating mononuclear cells. Detection of endogenous interferon-gamma and tumor necrosis factor-alpha in human colorectal adenocarcinomas.

Quantitative evaluation of the levels of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the extracts of tumors and their corresponding normal tissues resected from 43 patients with colorectal adenocarcinoma was done using solid-phase, sandwich radioimmunoassay. The levels of both IFN-gamma and TNF-alpha detected in the tumor tissues were higher than those in the corresponding normal colorectal tissues obtained from each patient. A significant negative correlation was observed between the level of IFN-gamma and TNF-alpha in each tumor extract. The decrease of the level of IFN-gamma in the tumor correlated with the advance of clinical stage, and the levels of IFN-gamma of the patients with distant metastases were significantly lower than those of the patients without distant metastases. However, an increase in the level of TNF-alpha correlated not only with an enlarged diameter but also with the extent of the primary tumor. Immunohistochemical staining of IFN-gamma and TNF-alpha producing cells in tumor tissues showed that IFN-gamma was mainly produced by CD4+ CD8- T-lymphocytes and TNF-alpha was mainly produced by CD11c+ cells with macrophage-like morphology. These results suggest that CD4+ T-lymphocytes that produce IFN-gamma might play an important role in the antitumor response against cancer progression in human colorectal adenocarcinomas.

Adenocarcinoma↗
PubMed1990

Expression of intercellular adhesion molecule-1 (ICAM-1) on renal-cell cancer: possible significance in host immune responses.

In this study we examined the expression of intercellular adhesion molecule-1 (ICAM-1) in 28 cases of renal-cell cancer (RCC). We also examined ICAM-1 expression on RCC cell lines in response to cytokines. Immunohistochemistry revealed frequent expression (23 positive cases among the 28 RCCs) of ICAM-1 in RCC. The molecule was not detected on renal tubular cells as far as could be determined. Furthermore, the number of ICAM-1-positive cells in RCC was significantly correlated with the degree of mononuclear cell infiltration, involving mainly T lymphocytes and a smaller number of macrophages bearing the LFA-1 molecule. Expression of ICAM-1 on RCC cell lines was augmented by in vitro treatment with interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and interleukin-1 (IL-1)beta. These results suggest that the expression of ICAM-1 on RCC might be modified by cytokines produced by tumor-infiltrating mononuclear cells, and that ICAM-1 expression on RCC might augment the host immune reaction.

Adult↗
PubMed1990

Functional analysis of mononuclear cells infiltrating into tumors: establishment of a new system to obtain functionally active tumor-infiltrating cells.

We have demonstrated that tumor-infiltrating T cells play a crucial role in tumor growth. In order to investigate the precise function of tumor-infiltrating cells, we avoided the use of any enzyme for separation of tumor-infiltrating cells from the solid tumor mass and established a new system in which we could easily obtain functionally active tumor-infiltrating cells in large amounts from the peritoneal cavity of T-9 gliosarcoma-sensitized rats. In this system, viable T-9 cells were intraperitoneally administered and peritoneal exudate cells were recovered. Importantly, cells obtained from the intraperitoneal cavity are phenotypically and functionally indistinguishable from those obtained from subcutaneous tumor masses. Furthermore, injection of purified lymphocyte migration factor-b resulted in the accumulation of CD8 (+) cytotoxic T cells in the peritoneal cavity. Therefore, this system also provides a means by which the in vivo function of chemotactic factor can be tested.

Animals↗
PubMed2026

A Phase II Feasibility Study Combining Pembrolizumab and Metformin in Patients with Metastatic Head and Neck Cancer.

PURPOSE: Survival for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains low with <20% immunotherapy response. Metformin increases tumor-infiltrating CD8+ T and natural killer (NK) cells, which harbor PD-1. In this phase II clinical trial (NCT04414540), we combined metformin and pembrolizumab to evaluate the overall response rate (ORR) in R/M HNSCC and assess NK-cell activity. PATIENTS AND METHODS: Eligible patients were randomized 1:1 into two arms: (i) metformin extended-release (ER) dose escalation to 2,000 mg over 14 days followed by combination with pembrolizumab 200 mg every 3 weeks or (ii) pembrolizumab 200 mg every 3 weeks followed by combination with metformin ER 2,000 mg daily. The primary endpoint was ORR per RECIST 1.1. Nineteen evaluable patients were planned to estimate the proportion of approximately 32% ORR. Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0. The distribution, activation, and cytotoxic function of NK cells were analyzed via flow cytometry. RESULTS: Twenty-one patients were enrolled; 76% were male, 52% were smokers, and the median age was 64 years. Ten patients had oropharyngeal tumors, of which nine were p16+. Eighteen patients were evaluable for response, including four complete and five partial responses for an ORR of 50% [95% confidence interval (29-71)]. Combination therapy was well tolerated with no unexpected adverse events (AE). Five grade 3 AEs occurred: nausea, diarrhea, fatigue, and weight loss. Metformin led to increased peripheral NK-cell maturation and cytotoxic ability. CONCLUSIONS: The combination of metformin and pembrolizumab was well tolerated with mild gastrointestinal AEs and promising activity, warranting further investigation in a randomized trial.

Humans↗
PubMed2026

Senescent fibroblasts drive CD8+ T cell dysfunction in colorectal cancer via CD36-mediated lipid transfer and peroxidation.

BACKGROUND: Functional exhaustion of tumor-infiltrating CD8+ T cells represents a hallmark of colorectal cancer (CRC) immunosuppression, though its mechanistic drivers remain elusive. Given the established correlation between CRC progression and stromal senescence characterized by pathological lipid accumulation and impaired immunity, we investigated whether and how senescent fibroblasts actively regulate CD8+ T cell dysfunction. METHODS: Single-cell RNA sequencing (scRNA-seq) analysis was conducted to unveil the diverse fibroblast populations and the significant lipid metabolism changes between senescent fibroblasts and non-senescent fibroblasts in human CRC specimens and adjacent normal mucosa. Machine-learning identified senescent fibroblasts with a distinct gene signature. Cell-cell communication analysis was used to evaluate the interactions between senescent fibroblasts and CD8+ T cells in colorectal cancer. Co-culture experiments were conducted among senescent fibroblasts, CD8+ T cells and patient-derived organoids of CRC (CRC-PDOs), with the results evaluated with high-content imaging and propidium iodide/Hoechst 33,342 staining. Flow cytometry, ELISA and lipid pulse-chase with BODIPY FL C16 were performed to detect the alterations of CD8+ T cell cytotoxic function and metabolic status. AOM/DSS-induced CRC mouse model was used to conduct in vivo validation to evaluate whether senolytics could suppress CRC progression. Patients from the Cancer Genome Atlas colorectal cancer cohort were stratified into CD36-high and CD36-low groups by median expression, and drug sensitivity for GDSC2 compounds was predicted computationally using the oncoPredict R package. RESULTS: ScRNA-seq demonstrated the specific cell population presence and divergence of senescent fibroblasts between neoplastic and histologically normal adjacent cell clusters in CRC. Random Forest was employed for cell senescence classification. Feature importance analysis identified five genes as key contributors to the model&#x2019;s decision process. Cell-cell communication analysis revealed enhanced interactions between senescent fibroblasts and CD8+ T cells in CRC. Co-culture of senescent fibroblasts significantly impaired the cytotoxic functions of CD8+ T cells on CRC-PDOs, which was reflected by the declined proportions of granzyme B (GZMB) + and interferon gamma (IFN&#x3b3;) + CD8+ T cells and enhanced viability of CRC-PDOs. Mechanistically, the co-culture with senescent fibroblasts promoted the lipid shuttling into CD8+ T cells to induce lipid peroxidation and downstream impairment of cytotoxicity. Furthermore, the inhibition of CD36, the specific scavenger receptor for lipid uptake of CD8+ T cells, effectively suppressed lipid transfer and peroxidation thereby preserving the effector functions of CD8+ T cells and ultimately promoting tumor apoptosis. Complementarily, in vivo senolytic treatment significantly suppressed CRC progression in AOM-DSS CRC mouse models. Top 12 therapeutic agents were identified significantly enhanced predicted efficacy in CD36-high tumors. CONCLUSIONS: Our study identified a substantial population of senescent fibroblasts in human CRC through single cell transcriptomics, machine-learning and clinical biopsies. These senescent fibroblasts impair CD8+ T cell-mediated killing of CRC-PDOs via CD36-dependent lipid transfer, suggesting senolytic targeting of stromal cells as a promising immunotherapeutic strategy for CRC.

Colorectal Neoplasms↗
PubMed1992

[Detection of endogenous IFN-gamma and TNF-alpha in tumor-infiltrating mononuclear cells of human colorectal cancer].

Quantitative evaluation of the levels of endogenous gamma-interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the extracts of tumor, peritumoral and normal colorectal tissues resected surgically from 43 patients with colorectal adenocarcinoma was carried out using solid-phase, sandwich radioimmunoassay (RIA). The levels of both IFN-gamma and TNF-alpha detected in the tumor tissues were higher than those in the peritumoral and normal tissues obtained from each patient. A significant negative correlation was observed between the levels of IFN-gamma and TNF-alpha in each tumor tissue. The decrease of endogenous IFN-gamma in the tumors correlated with the advance of histopathological stages. Thirty seven patients were classified into three types according to the endogenous IFN-gamma distribution (intratumoral dominant type, peritumoral dominant type and nonreactive type). There was no significant difference concerning to the tumor diameters among them. However, the mean stage of the intratumoral dominant type was significantly earlier than that of the nonreactive types. On the other hand, the increase of endogenous TNF-alpha correlated with the maximum diameter of primary tumors. The production of endogenous TNF-alpha was localized in the tumor tissues, and the significant elevation of endogenous TNF-alpha was not observed in the peritumoral tissues. The immunohistochemical staining of IFN-gamma- and TNF-alpha-producing cells in tumor tissues represented that IFN-gamma was mainly produced by CD4+CD8-CD11c- lymphocytes and that TNF-alpha was mainly produced by CD4-CD8-CD11c+ cells with macrophage-like morphology. These results suggest that CD4+ lymphocytes producing IFN-gamma might play an important role in the anti-tumor response against cancer progression in human colorectal adenocarcinoma.

Adenocarcinoma↗
PubMed1991

In situ localization of 3.2.3+ natural killer cells in tissues from normal and tumor-bearing rats.

A monoclonal antibody, designated 3.2.3, which recognizes a novel Mr 60,000 disulfide-linked lytic triggering structure present on rat large granular lymphocytes and natural killer (NK) cells was recently described (W. H. Chambers et al., J. Exp. Med., 169: 1373-1389, 1989). The present study describes the use of 3.2.3 to identify the in situ tissue distribution of large granular lymphocytes/NK cells in different organs from normal and tumor-bearing F344 rats. Frozen tissue sections were prepared and stained with monoclonal antibody 3.2.3 using an avidinbiotin immunoperoxidase technique. 3.2.3+ NK cells were easily identified using this technique, and quantitative analysis of various tissues of normal rats demonstrated that (a) in the spleen, most NK cells were located, sometimes as aggregates, in the red pulp (12.4% of total nucleated cells in that organ compartment) with relatively few noted in the white pulp (0.2-2.3%); (b) in the liver, 3.2.3+ cells were rare, sparsely distributed, and located primarily in the sinusoids (1.2%); (c) in the lungs, 3.2.3+ cells were located in the interstitium (3.7%); (d) in the thymus, 3.2.3+ cells were found primarily in the medulla (1.8%) adjacent to the cortex but not in the cortex itself (0.2%); (e) in the lymph node, most 3.2.3+ cells were contained in the paracortex (6.9%); and finally (f) in the small bowel, 3.2.3+ cells were present in the lamina propria (8.6%) and as aggregates in the interfollicular zone of Peyer's patches (0.7%). To study the distribution of 3.2.3+ NK cells in developing tumor metastases, we induced liver metastases by intrasplenic injection of MADB106 mammary adenocarcinoma cells and prepared frozen tissue sections of the liver 10-14 days later. We found that the frequency of 3.2.3+ cells in the developing liver metastases was 3-6 times higher than in the surrounding normal liver tissue. Moreover, the frequency of 3.2.3+ NK cells was equivalent to the frequency of tumor-infiltrating CD5+ T-cells identified in the same tumor lesions. This suggests specific infiltration of 3.2.3+ NK cells in early developing metastatic lesions. These results indicate that monoclonal antibody 3.2.3 will be valuable in analyzing the involvement of NK cells in various pathological states.

Adenocarcinoma↗