T‐Cell Clones that react against Autologous Human Tumors

Abstract

T cells (derived from peripheral blood lymphocytes [PBL], lymph nodes or tumor tissues and restimulated with autologous tumor cells and expanded in interleukin-2 [IL-2]), when cloned, produce three functional classes of clone. Class I T-cell clones exhibit the phenotype of alpha/beta cytotoxic T lymphocytes (CD3+, CD8+, CD4-, WT31+), use their CD3-alpha/beta complexes for cognate function, and lyse the autologous tumor cells specifically in a major histocompatibility complex (MHC) Class I-restricted manner. The second class of T cell clone expresses identical phenotype but exhibits a rather broad cytotoxic profile against the autologous and allogeneic tumor cells derived from tumors with similar and/or dissimilar histologies. Although these CTL clones can, at times, show MHC Class I-restricted killing and use their T-cell receptors (TCR) complexes for function, activation via certain accessory molecules, particularly lymphocyte-function associated (LFA-1) antigens, might induce their broad cytotoxic behavior. The nature of the tumor antigen recognized by the Class I antigen-specific CTL clones remains unknown. It is evident, however, that more than one antigen can be associated with a given tumor and they are recognized by different CTL clones from individual patients. The third class of T-cell clone is usually of CD4+ alpha/beta T cells (CD3+, CD4+, CD8-, WT31) and these T-cell clones exhibit no cytotoxicity toward the autologous or allogeneic target cells. When tested for potential regulatory property, one type of CD4+ T-cell clone exhibits the characteristics of helper T cells. This type induces or amplifies cytotoxic response in fresh PBL by elaborating interleukin-2 (IL-2) and interferon-gamma). These helper T-cell clones can proliferate against the autologous tumor cells and demonstrate functional specificity for the autologous tumor cells. The other type of CD4+ T-cell clone exhibits the phenotype of the helper T-cell clone (CD3+, CD4+, CD8-, WT31+) but suppresses the cytotoxic response of the autologous PBL in co-culture in the presence of the autologous tumor cells and exogenous IL-2. In some situations, these CD4+ suppressor T-cell clones exhibit considerable specificity for the autologous tumor cells. They do not suppress the cytotoxic response against allogeneic targets or against EBV-infected autologous lymphoblastoid cells. Furthermore, they specifically up-regulate their IL-2 receptors (IL-2R) when stimulated by the autologous tumor cells or with autologous tumor cell-pulsed antigen-presenting cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Lack of HLA class I antigen expression by melanoma cells SK-MEL-33 caused by a reading frameshift in beta 2-microglobulin messenger RNA.

“…Amplified DNA was analyzed by nondenaturing agarose gel electrophoresis. 5 Al of the amplification reaction was electrophoresed on a 1.5% Tris-Borate-EDTA agarose gel (FMC Corp., Rockland, ME) in the presence of ethidium bromide.…”

“…The latter include reduction or loss of HLA class I antigen expression, which has been found to occur in -30% of surgically removed melanoma lesions (for review, see reference 1). Abnormalities in HLA class I antigen expression are likely to affect the biology of melanoma cells and their interactions with immune cells be-cause of the role of HLA class I antigens in cell proliferation (2)(3)(4), interaction of target cells with cytotoxic T cells (for review see reference 5), and susceptibility of malignant cells to natural killer (NK)' cell-mediated lysis (for review see reference 6). Besides contributing to the characterization of the machinery regulating HLA class I antigen synthesis and expression, analysis of the molecular mechanisms underlying reduction or loss of HLA class I antigen expression by melanoma cells provides the necessary background to correct these abnormalities.…”

Analysis of T cell receptor variability in tumor-infiltrating lymphocytes from a human regressive melanoma. Evidence for in situ T cell clonal expansion.

“…Many in vitro studies have shown the existence of specific immune interactions: cultured T cells derived either from PBL, lymph node, or the site of the tumor were found to display specific MHC-restricted regulatory or effector activities in response to autologous melanoma cells (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Encouraging results have been obtained with ex vivo expanded tumor-1.…”

IL-4 Protects Tumor Cells from Anti-CD95 and Chemotherapeutic Agents via Up-Regulation of Antiapoptotic Proteins

“…The antitumor immune response is predominantly sustained by tumor-infiltrating T lymphocytes (TILs), consisting of CD4 ϩ and CD8 ϩ T cells (15). CD4 ϩ Th lymphocytes have been divided into Th1 and Th2 subpopulations, based on their functional properties and on the profile of secreted cytokines.…”