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PubMed1992

[Sensitivity test to chemotherapeutic agents and cytotoxicic test against immuno-effecter cells of established malignant fibrous histiocytoma cell line].

UNLABELLED: A cell line was established from a patient with malignant fibrous histiocytoma, which had originated in the maxillary sinus. Using this cell line, sensitivity to chemotherapeutic agents and cytotoxicity against various immunoeffecter cells were tested. RESULTS: This MFH cell line was sensitive in some degree to adriamycin, 5-fluorouracil, cisplatin, peplomycin, and methotrexate at high doses, but insensitive to mitomycin-C, vincristine and cyclophosphamide. Furthermore, this cell line showed no sensitivity to cytolytic cytokines, such as tumor necrosis factor-alpha and interferon-gamma. Lymphokine activated killer (LAK) cells and lymphokine activated tumor infiltrating lymphocytes (LA-TIL), induced by culture of peripheral blood lymphocytes and TIL respectively with rIL-2 showed high NK and LK activities and remarkable anti-autologous tumor ability.

Antineoplastic Agents↗
PubMed1992

[Malignant lymphomas of soft tissues].

Among annually 1000 consultation cases of soft tissue tumors, minimally 1.2% to maximally 2% malignant lymphomas could be identified, which presented as (primary) soft tissues tumor. Thus malignant lymphoma as soft tissue tumor is rare, however, it has to be considered in differential diagnosis not only of cellular round cell sarcoma, but also with undifferentiated carcinomas (large cell Ki-1 lymphomas) and various myxoid spindle cell sarcomas (sarcomatoid lymphoma). Decisive in differential diagnosis were decorations with pan-leucocyte antibody, as well as, B- and T-cell markers. All cases turned out to be non-Hodgkin lymphomas, the majority of B-cell type, with large cells which qualified as centroblasts (according to Kiel classification). Similar findings, predominance of B-cell non-Hodgkin lymphomas with large cells, were reported in the few series published of malignant lymphomas as soft tissue tumors. Remarkable were relatively good prognosis with "highly malignant" morphology and preference for involvement of soft tissue even after dissemination. Future studies are requested to shed light on possible specific cellular findings as to phenotype and genotype in malignant lymphoma presenting as soft tissue tumors, as already had been done with subcutaneous T-cell lymphoma and primary lymphoma of the bone.

Female↗
PubMed1992

[Demonstration of Epstein-Barr virus DNA and determination of immunoglobulin and T-cell receptor gene rearrangerments in diagnostic lymph node biopsies from patients with Hodgkin's disease].

Lymph node biopsies of 52 patients with Hodgkin's disease were analyzed by Southern blot hybridization for the presence of monoclonal rearrangements of immunoglobulin and T cell receptor genes. The same tissues were tested for Epstein-Barr virus DNA by the polymerase chain reaction using four different sets of primers. Monoclonal rearrangements were identified in only four tumors, whereas Epstein-Barr virus was present in 79% of biopsies. A correlation between the degree of infiltration by Reed-Sterberg cells, clonality and the presence of Epstein-Barr virus could not be found. These results are in agreement with similar studies reported in the literature. The nature of the malignant cell in Hodgkin's disease and the role of Epstein-Barr virus in the etiology of this tumor remains to be established.

Base Sequence↗
PubMed1992

[Hodgkin's disease--an entity?].

Since 26 years Hodgkins disease is classified according to the Rye classification into 4 types. This classification is based on morphology and has turned out to be clinically relevant. However, sometimes the classification on morphological and immunohistochemical ground can be difficult to put a special case in a defined category of the 4 types. In addition, there seems to be no sharp, or well defined borders between Hodgkin's disease and Non-Hodgkin's lymphomas, especially T-cell lymphomas. Immunophenotyping of small lymphocytes and detection of follicular dendritic cells can demonstrate typical patterns in different types of Hodgkin's disease. In all types of Hodgkin's disease there is the same amount of proliferating small T-cells present. Hodgkin cells are lymphoid cells with B- or T-cell markers. Hodgkin cells of nodular para-granuloma (lymphocyte predominant type of Hodgkin's disease) show m-RNA for one light chain in the cytoplasm which can be visualized by in situ-hybridization. A new technique called "molecular histology" is applied to Hodgkin's disease. This is a single cell PCR of immunostained cells extracted from tissue sections by a micromanipulator. This technique enables us for the first time to demonstrate light chain and heavy chain gene rearrangements in Hodgkin cells of nodular sclerosis and mixed cellularity type. Hodgkin's disease seems to be no single entity but a heterogenous group of B- and possibly T-cell lymphomas. In the B-cell types Hodgkin cells are probably pre-B and B-cells.

Chromosomes, Human, Pair 14↗
PubMed1992

[Autoimmune diseases and malignant lymphoma].

During the recent decade evidence accumulated, that autoantibodies exist with a high frequency in the normal B-cell repertoire. The autoreactive B-cell repertoire may undergo malignant transformation through the continuous challenge by autoantigen. Previous work on human paraproteins of plasmocytoma and immunocytoma has shown that a high proportion of paraproteins bind to self determinants. B-cell lymphoma may mimic the lesions in organotropic autoimmune disease, eg. Sjögren's disease, Hashimoto's thyroiditis and coeliac disease by the neoplastic expansion of autoimmune receptors. Considerable evidence has been obtained, that the specific receptor interactions of the lymphoma with the autoantigen may be of functional significance. More precise knowledge on receptor specificities would permit new approaches to the understanding and manipulation of autoimmune disease and lymphoma.

Autoantigens↗
PubMedDate not supplied

[Lymphocytic infiltration in cerebral gliomas].

The authors analyse the incidence, extent and prognostic significance of lymphocytic infiltration in 80 cases of operated cerebral gliomas (61 high- and 19 low-grade gliomas). The results obtained are discussed in relation to the data previously reported by the literature.

Astrocytoma↗
PubMed1992

[T-cell receptor repertoire in tumor infiltrating lymphocytes within malignant brain tumors].

Expression of T cell receptor (TCR) V alpha and V beta genes in tumor infiltrating lymphocytes (TILs) within human malignant brain tumor was examined. Primers for 18 different human TCR V alpha and 21 V beta families were used to analyze TCRV-(D)-J-C gene rearrangements in TILs in 8 human malignant glioma specimens obtained at surgery. Using the polymerase chain reaction (PCR) method, we detected limited TCR variable region, V alpha gene expression in malignant glial tumors and also V alpha 7 and V alpha 12 TCR genes were preferentially expressed. Usage of TCR V beta gene was not as restricted as in TCR V alpha. These TILs expressing a limited repertoire of TCRs might be isolated, expanded, and used therapeutically for treatment of malignant brain tumors.

Adolescent↗
PubMed1992

[Experimental studies on the antitumor activity of glioma-infiltrating lymphocytes against autologous glioma].

In the present study, antitumor activity of glioma-infiltrating lymphocytes (GILs) was compared to that of lymphokine-activated killer (LAK) cells. Results suggested that killing activity of GILs against autologous glioma cells was significantly higher than that of LAK cells (P less than 0.05), but their activity against allogeneic glioma cells was not different from that of LAK cells (P greater than 0.05). Analysis of cell surface phenotypes showed that CD4+ cells were a main portion of LAK cells, and CD8+ were predominant in the GILs. In the beginning, growth of GILs was slower than that of LAK cells. As time went on, generation of GILs was faster than that of LAK cells. The results suggested that GILs were superior to LAK cells for adoptive immunotherapy in patients with brain glioma.

Brain Neoplasms↗
PubMedDate not supplied

[Evaluation of prognostic parameters in colorectal carcinoma. I. Histopathological variability].

A careful histopathological analysis was performed on a series of 244 unselected surgically removed primary colonic and rectal cancers. Tumours were staged according to the TNM system. Tumour type (adenocarcinoma or mucinous carcinoma), grade of differentiation, character of invasive margin, degree of peritumoural lymphocytic infiltration, venous and neural invasion were found to be correlated with the clinico-pathological stage and in some ways interrelated. As a whole our results seem to suggest that histological evaluation of the variables examined may provide information of clinical relevance in the management of patients with large bowel cancer.

Adenocarcinoma↗
PubMed1992

[New aspects of adoptive immunochemotherapy in disseminated forms of cancer].

A method of autolymphochemotherapy was developed based on administration of a "therapeutic" course of chemotherapy following cytotoxic treatment of a large amount (1.5-2 l) of central lymph obtained by external drainage of the thoracic duct. Immediate results of treatment of 15 patients with advanced breast, lung (non-small-cell) and ovarian cancer with various degree of chemoresistance are presented. Marked response was observed in 14 cases. It seems justified to use the method for the treatment of locally advanced cancer.

Adult↗
PubMedDate not supplied

[Significance of intratumoral leukocytes in the local immune reaction in squamous cell carcinoma of the lower lip].

50 cases of squamous cell carcinoma of the lower lip were analyzed histologically. Surgical specimens were examined for presence tumor-infiltrating leukocytes and pattern of stromal invasion. The estimation of the characteristics of local immune reaction was performed at the interface of the tumor and underlying tissues at the site of deepest penetration. As a result, there was a significant inverse correlation between degree of tumor-infiltrating leukocytes and pattern of invasion. Marked of tumor-infiltrating leukocytes is a manifestation of efficiently host immune response to the tumor.

Adult↗
PubMed1992

Reaction patterns of tumor infiltrating lymphocytes in different renal cell carcinomas and oncocytomas.

1. Only clear cell and chromophilic carcinomas of the kidney exhibit a considerable lymphocytic infiltration which is compatible with some immunological responsiveness. Chromophobic carcinomas and benign oncocytomas seem to be immunologically reactive. This reflects the different antigen spectrum and histogenesis of these tumors (Störkel and Jacobi, 1989). Clear cell and chromophilic carcinomas are derived from the proximal tubule and chromophobic carcinomas and oncocytomas from the collecting duct. 2. The tumor periphery seems to be the place of greatest immunological importance, as basic requirements of a sufficient lymphocyte/tumor cell interaction can only be expected there. If these data are taken into account for a therapeutical approach with biological immune modifiers the size of the tumor (tumor burden) and proliferation index must be considered too. This might be a likely explanation for the positive effect of inhaled interleukin-2 on lung metastasis in renal cell cancers. Harvesting of tumor infiltrating lymphocytes for therapeutical purposes should take these findings into account. 3. In spite of dense lymphocytic infiltration only 3% of the tumor infiltrating lymphocytes exhibit the activation marker CD 25. There seems to be a sufficient T cell locomotion in renal cell carcinomas but an insufficient T-cell activation. Whether this fact is induced by lacking cytokine stimulation of involved lymphocytes or by still unknown mediators of the tumor cells is not yet known and needs further investigation. 4. Clear cell carcinomas exhibit most adhesion molecules and the highest amount of infiltrating cytotoxic T-cells and natural killer cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1992

HLA class II antigen expression in human papillomavirus-associated cervical cancer.

The observation that tumor cells of some neoplasms display major histocompatibility complex (MHC) class II molecules may be of functional significance, influencing the progression of malignancy by allowing the cancer cells to present antigen to the immune system. In the normal cervix, class II molecules are expressed by columnar but not squamous epithelium. The pattern of MHC class II expression in cervical carcinomas has been documented using immunohistochemical methods. Of 53 cervical squamous carcinomas examined for MHC class II expression, only 17% maintained a negative phenotype characteristic of the epithelium from which they were derived, while the remaining tumors exhibited either uniform (45%) or heterogeneous (38%) expression. Tumor areas which were class II positive also express class II associated invariant chain and the adhesion molecules lymphocyte function antigen 3 and intercellular adhesion molecule 1. The DR, DP, and DQ class II MHC subloci are differentially expressed, suggesting independent regulation. There is a trend for tumors with the uniform class II phenotype to predominantly express DR antigen, whereas tumors of the heterogeneous class II phenotype express with equal frequency either DR or DP antigens dominantly. There is no apparent influence of class II status on lymphocyte infiltration of the tumors. The presence of human papillomavirus 16 DNA in the cervical carcinoma specimens was analyzed by Southern blotting of restriction enzyme digested DNA and no correlation between the presence of human papilloma virus and MHC class II expression was found.

Adult↗
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↗
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↗