Future Research Directions to Improve Functional Cytotoxicity of Tumorspecific CTLs

Until the near past, much effort was invested in generating ample amounts of tumor-specific T cells. The quantitative barrier was considered a major obstacle to achieve tumor regression. The feasibility of ex vivo T cell expansion allowed the clinical use of selective tumor-reactive T cells out of TILs and PBMCs [79]. The progress made in TCR gene transfer into T cells is now enabling the selection of high affinity TCRs in order to produce large numbers of antigen-specific T cells [80]. This technology will eventually bring to an end the dependency on preexisting effectors necessary to establish T cell lines for treatment. Clearly, a major goal of research over the next years will be to increase the tumor destructive properties of CTLs, making them better killers and less vulnerable to the consequences of activation. Gene transfer opens exciting possibilities for T cell manipulation beyond the TCR. This tool, and the emerging new monoclonal antibodies that act to restore T cell functions in cancer patients, may change the outlook for tumor immunotherapy.

Critical elements affecting tumor-T cell interaction are potential targets for intervention. Because lytic functions are dependent on TCR signaling [81], a primary goal would be to enhance TCR-pMHC interaction directly or through the establishment of a stable IS. So far, the strategy employed was to strengthen pep-tide-MHC complex using improved antigenic epitopes with high affinity binding to MHC molecules. TCR signaling may be directly augmented, independent of the binding affinity to its antigenic peptide. For example, the use of miR 181a may augment TCR sensitivity to threshold levels of ligand, and enhance T cell cyto-toxic activity [53]. Stabilizing the immune synapse could yield stronger TCR signaling, for example by increasing LFA1 expression on CTL. Using a different strategy, one could endow T cells with improved resistance to apoptotic signals through transfer of anti-apoptotic genes, such as Bcl-2 [82]. Most encouraging, clinical trials recorded objective cancer regressions achieved by anti-CTLA-4, a blocking antibody that antagonizes suppressive signals and unleashes CTLs [83]. Once again the potency of cytotoxic T cells for the destruction of malignant tumors was shown.

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