ABSTRACT
Even though renal cell carcinomas (RCC) are thought to be immunogenic, many tumors express variations in surface molecules and intracellular proteins that hinder induction of optimal antitumor responses. Interferon gamma (IFNgamma) stimulation can correct some of these deficiencies. Therefore, we introduced the complementary DNA (cDNA) encoding human IFNgamma into a well-characterized RCC line that has been selected for development of an allogeneic tumor cell vaccine for treatment of patients with metastatic disease. Studies were performed to determine how endogenous IFNgamma expression influences tumor cell immunogenicity. IFNgamma transductants showed minimal increases in surface expression of MHC class I and adhesion molecules but expression of class II molecules was induced. Proteins of the transporter associated with antigen processing (TAP) and low molecular weight polypeptide (LMP) were constitutively expressed at high levels. The transductants stimulated allospecific cytotoxic T lymphocytes (CTL); however, they were not better than unmodified tumor cells in this capacity. Endogenous IFNgamma expression enhanced tumor cell recognition by MHC-restricted, tumor antigen-specific CTL but suppressed recognition by non-MHC-restricted cytotoxic cells. Thus, the functional consequences of IFNgamma expression varied with respect to the type of effector cell and were not always beneficial for tumor cell recognition.
Subject(s)
Cancer Vaccines/administration & dosage , Carcinoma, Renal Cell/therapy , Cysteine Endopeptidases , Interferon-gamma/genetics , Kidney Neoplasms/therapy , Multienzyme Complexes , T-Lymphocytes, Cytotoxic/immunology , Transfection/methods , ATP Binding Cassette Transporter, Subfamily B, Member 2 , ATP Binding Cassette Transporter, Subfamily B, Member 3 , ATP-Binding Cassette Transporters/genetics , Carcinoma, Renal Cell/immunology , Cell Adhesion Molecules/metabolism , DNA, Complementary , Fluorescent Antibody Technique, Indirect , Gene Expression , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class II/metabolism , Humans , Kidney Neoplasms/immunology , Luminescent Measurements , Proteasome Endopeptidase Complex , Proteins/genetics , Tumor Cells, CulturedABSTRACT
Renal cell carcinomas belong to the small group of tumors that are able to induce antitumor responses. Here we describe two general types of cytotoxic effector lymphocytes that can eliminate autologous tumor cells and discuss the role that major histocompatibility complex encoded molecules play in governing their specificities. Improved understanding of the cellular and molecular basis of renal cell carcinoma recognition opens new avenues of research with the potential to develop better immunotherapies for patients with metastatic disease.
Subject(s)
Antigen-Antibody Reactions , Carcinoma, Renal Cell/therapy , Immunotherapy , Kidney Neoplasms/therapy , Major Histocompatibility Complex/immunology , T-Lymphocytes, Regulatory/immunology , Humans , Killer Cells, Lymphokine-Activated/immunologyABSTRACT
The intercellular adhesion molecule-1 (ICAM-1) is important in mediating intercellular contact in inflammation. Therefore, we have analyzed the expression of this molecule on alveolar macrophages (AM) and in serum of patients with sarcoidosis. Bronchoalveolar lavage (BAL) cells from 13 patients and 11 control donors were stained with an anti ICAM-1 monoclonal antibody (mAb) or an isotype control. Alkaline phosphatase was used as a detection system, followed by digital single cell image analysis. Soluble ICAM-1 in serum (ssICAM-1) was determined by enzyme linked immunoassay (Elisa). Immunocytochemistry revealed a strong increase of ICAM-1 expression on AM from sarcoidosis patients (64%) compared to healthy controls (30%). Furthermore, patients exhibited a fourfold higher antigen density. Serum levels of sICAM-1 were more than twofold increased in the patient group (805.4 micrograms/ml) compared to healthy controls (384.8 micrograms/ml). SsICAM-1 showed an inverse correlation with vital capacity (VC) and diffusing capacity (DCO). This significant correlation with impairment of two important lung function parameters suggests that ssICAM-1 might be useful in serological assessment of disease activity in sarcoidosis.