Mechanisms of syngeneic tumor rejection. Susceptibility of host-selected progressor variants to various immunological effector cells.

Abstract

The ultraviolet radiation-induced fibrosarcoma 1591 generally is rejected by normal syngeneic mice and only rarely exhibits progressive growth. We isolated five of these rare progressor tumors from normal animals to determine the selective pressures that had been exerted upon the parental tumor by normal immunocompetent hosts. We found that the variant tumor cell lines could neither induce nor be killed by tumor-specific lymphocytes, suggesting that selection had been exerted against tumor cells expressing the tumor-specific antigen. In contrast, no selection against natural killer cell activity or against nonspecific T cell-mediated immunity seems to have occurred because progressor tumor cells were highly sensitive to these types of effector cells and in fact induced these effector cells more effectively than did the parental tumor. Nude mice were found to be as capable as normal mice in generating natural killer activity in response to a challenge with progressor tumor cells, but they were unable to mount a nonspecific T lymphocyte response. This may account for the fact that the progressor tumors grew at a significantly faster rate in nude animals than in normal mice. Thus, our study shows that in this tumor system nonspecific T cell-mediated immunity may play a role in retarding tumor growth, but the absolute resistance of normal animals to progressive tumor growth critically depends upon the presence of T cell-mediated tumor-specific immunity. Furthermore, neither NK cells nor nonspecific cytotoxic T lymphocytes appear to play a role in immunoselection against this tumor in normal immunocompetent hosts.

Immunological competence of patients in remission from acute leukaemia: apparently normal T cell function but defective pokeweed mitogen‐driven immunoglobulin synthesis

“…Cell-mediated immunity is believed to be of major importance in the defence against viral and certain intracellular bacterial pathogens (14) as well as immunogenic tumours (e.g., (15)). Therefore, adequate T cell function is likely to be essential for Ihe effectiveness of specific anti-leukaemia immunotherapy, as well as for the safe use of live, attenuated microbial vaccines.…”

Highly malignant tumor variants retain tumor-specific antigens recognized by T helper cells.

“…These variants grow progressively upon subsequent transplantation in -80% of young immunocompetent mice (2), and they kill the host through local invasion, without macroscopic evidence of distant metastases . As a result of immunoselection by the normal host, the 1591-PRO variants have lost a 1591-tumor-specific antigen (designated A) that is only expressed on 1591-RE tumors (7,8) .…”

“…Regression occurs even when large doses of the tumor are injected, e .g., multiple 1-mm 3 tumor fragments, while much smaller tumor grafts grow progressively and kill immunodeficient or nude mice (11) . Noncrossreacting, tumor-specific antigens have previously been shown on these tumors using transplantation assays (11), and through the generation of CTL (2,10,12) and mAb probes (13) .…”

“…After 7 d of incubation, we resuspended cultures by pipetting, and we split two 150-,1 aliquots to corresponding wells of two microtitration plates to which we added the specific or an unrelated "Cr-labeled tumor target in 50 j1 medium . In some experiments, the phenotype of responder cells was assayed by depletion of Thy-1 .2 + or Lyt-2 + cells before culture using the AT83A or 3 .155 mAb and rabbit complement, as described (2) . In other experiments, the ability of anti-1-A', anti-L3T4, or anti-thy-1 .2 antibody to functionally block precursor Th activity by addition to microcultures in the absence of complement was assayed with or without the addition of supernatant containing added IL-2 .…”

“…To generate CTL, spleen cells from tumor-immunized animals were restimulated in vitro in a 7-d MLTC (2) . Continuous anti-1591 (anti-A) and anti-2240 CTL, lines were derived by cloning the CTL generated in MLTC with mitomycin C-treated tumor cells as stimulator cells, irradiated (2,000 rad) spleen cells as fillers cells, and a supernatant from secondary mixed lymphocyte cultures as a source of IL-2 (8) .…”