The role of cell-mediated cytolysis in antitumor responses

The purpose of the work described in this thesis was (1) to study the effector cell types involved in antitumor responses; (2) to investigate whether of the immune system in cancer patient may occur at tumor-target or at lymphocyte-effector cell level; and (3) to explore new strategies for producing tools for immunotherapy of cancer, i.e. enhancement of cytotoxic activity to optimal levels by BRM, and production of immortalized cytotoxic lymphocytes with stable lytic functions. The major conclusions that can be drawn from the results obtained are the following: 1. From the three lymphoid (sub) populations studied i.e. TCR-/CD3- NK, TCRa~+/CD3+ and TCRyo+/CD3+ CTL clones, TCRyo+/CD3+, TCRa~+/CD3+ CTL appeared to have the widest target cell spectrum and to exert the highest level of CTX against fresh tumor cells. 2. The failure of the immune system in the cancer patients we studied seems located at the level of the CDS+ lymphocyte, possibly tumor cell induced. This may be due to a defective signal transduction mechanism. 3. Cytolytic activity of TCR-/CD3- NK and TCRa~+/CD3+ T-cell clones against tumor cells can be successfully enhanced, i.e. lymphocyte clones that were already active could be stimulated further by OK-432 and IL-2. 4. In an attempt to immortalize cytotoxic lymphocytes by somatic cell hybridization, an efficient electrofusion system was developed for the first time, allowing to produce T- and NK-cell hybridomas routinely. In spite of the large number of hybridomas generated, only a few were transiently cytolytic. This is most likely due to chromosomal instability of the hybridomas. As suggested by our studies and those of others, DNA-mediated transfer of multiple genes, for instance e-ras, c-myc, PS3 and the IL-2R gene, involved in cell differentiation and proliferation may be an alternative strategy to immortalize cytotoxic lymphocytes.