A Murine Model for B-Cell Lymphomagenesis in Immunocompromised Hosts: Natural Killer Cells Are an Important Component of Host Resistance to Premalignant B-Cell Lines

Department of Pathology, UCLA School of Medicine 90024.
Cancer Research (Impact Factor: 9.33). 12/1990; 50(21):7050-6.
Source: PubMed


The accompanying paper (D. W. Felsher et al., Cancer Res., 50:7042-7049, 1990) describes a new panel of cloned murine B-cell lines with a premalignant phenotype and in vivo-derived malignant variants. This paper assesses the contribution of immune mediated antitumor mechanisms which might account for host resistance to the tumorigenicity of these cell lines. Conventional T-cell-dependent responses did not appear to be critical to host resistance. In vivo elimination of T-helper cells with anti-L3T4 monoclonal antibody did not reduce host resistance to the tumorigenicity of these cell lines, nor did these cell lines elicit cytotoxic T-cell activity. However, a strong correlation was found between tumorigenicity and host natural killer (NK) activity. In vitro studies demonstrated that the cell lines were as NK sensitive as the prototypical NK target, YAC-1, whereas the malignant variants fully tumorigenic in normal hosts were greater than 20-fold less NK sensitive than were the parent cell lines. In vivo depletion of NK cells with anti-asialo-GM1 in BALB/c strongly diminished host resistance to cell line tumorigenicity, whereas polydeoxyinosinic-deoxycytidilic acid induction of NK cells enhanced host resistance. These findings indicate that NK function is a critical component to host resistance in this system and suggest that endogenous cellular mechanisms which overcome NK sensitivity could be a target for secondary transforming events in B-cell lymphomagenesis. They also raise the unexpected possibility that a non-antigen-dependent (versus immune cytotoxic T-lymphocytes) effector mechanism may be the key deficit promoting B-cell neoplasia in the setting of immunocompromised states.

Download full-text


Available from: Dean Felsher
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Activation of c-myc or bcl-2 protooncogene is a common event in B-cell lymphomagenesis. Alone, each is insufficient to produce lymphoma, prompting the search for the additional steps required to complete the malignant phenotype. Among the existing systems of murine or human B-cell neoplasia, no commonly occurring complementary oncogenic activation has been found. This study introduces a new series of murine B-cell lines with a phenotype suggesting that such additional events might not involve intrinsic growth control, but instead host immune mechanisms which normally suppress tumorigenicity of premalignant B-cells. Four murine B-cell lines were isolated from the long-term culture of normal lymphoid tissue bearing a premalignant phenotype. (a) Their phenotype resembled naturally occurring lymphoid tumors of immunocompromised hosts with regard to c-myc activation, aberrant or absent immunoglobulin expression, preferential rearrangement of the lambda light chain locus, and a distinctive pattern of tissue invasion and tumor histology. (b) Their tumorigenicity was strictly dependent on host permissiveness correlated with immunodeficient status: C.B-17-scid greater than BALB/c-nu/nu greater than normal BALB/c much greater than other H-2d strains (NZB x NZW F1, NZB, DBA/2). (c) Host passage selected for malignant variants distinguished by a 10(4)-fold increase in tumorigenicity (as judged by limiting cell dose) and by novel tumorigenicity in nonpermissive syngeneic hosts. These features are analogous to properties of human lymphomas arising in immunocompromised states and, to our knowledge, unique among previously reported murine B-cell lines.
    Full-text · Article · Dec 1990 · Cancer Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study shows that the ability of mice to produce tumor necrosis factor (TNF), alpha/beta interferon (IFN-alpha/beta), and interleukin 6 (IL-6), but not interleukin 1 (IL-1), in response to endotoxin was dramatically augmented within 24 h of intradermal implantation of 10(6) tumor cells. Tumor cell implantation also caused endotoxin-independent appearance of IFN-alpha/beta and IL-6 in serum within 24 h. Priming for endotoxin-induced TNF production was not evident during the first 12 h of tumor cell implantation and it had decreased by 72 h. However, this decrease was followed by a second peak of priming on day 6 of tumor growth. Priming for endotoxin-induced TNF production was not induced by injection of dead tumor cells, the products of live tumor cells, or syngeneic or allogeneic splenocytes. Priming for TNF production was associated with an increased susceptibility of mice to endotoxin toxicity. These data suggest the existence of a cytokine-dependent host defense mechanism that is rapidly elicited in response to tumor cell implantation.
    No preview · Article · Oct 1991 · Cytokine

  • No preview · Article · Feb 1992 · European Journal of Cancer
Show more