Local immunostimulation leading to rejection of accepted male skin grafts by female mice as a model for cancer immunotherapy
(2016)
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- Abstract
- (en) The introduction is a review of the literature covering the different immunotherapeutic protocols tested within clinical trial for human practice. It has been shown that many cancer patients are able to mount a spontaneous T lymphocyte response against their tumor. In metastatic progressing patients, this response has evidently been incomplete. An increasing number of data on human tumors and tumor infiltrating lymphocytes support the scenario of an immunosuppressive environment that appears to be present within the tumor. This immunosuppressive environment seems to be a major factor preventing the success of immunotherapies, especially for anti-cancer vaccination. Our working hypothesis is that reversing focally the immunosuppressive environment to an immunostimulating environment could potentiate the effect of anti-cancer vaccination and other immunotherapeutic approaches such as immunostimulating antibodies (as anti CTLA-4). Stalled immune responses are occasionally observed in the area of tissue transplantation where a small number of recipients can be withdrawn from treatment with immunosuppressive agents without deleterious effects on the grafted organ. In a mouse strain named CBA, this phenomenon is observed when male skin is grafted onto females. Female of this mice strain do not reject syngeneic male skin grafts even though they mount a T cell response against the male-specific HY antigen. This experimental model was used to test our working hypothesis. In our skin graft model we have tested several agents that, when applied locally, may relieve the immunosuppression and reactivate the immune response leading to graft rejection. Some cytokine combinations, locally administered, are effective in promoting the rejection of these skin grafts. Local immunostimulation performed by injecting a combination of cytokines and Toll-like receptor ligands in close vicinity to the graft promoted rejection. This approach was then tested in a few tumor-bearing human patients in combination with anti-tumor vaccination. A clinical phase I/II trial based on the combination discovered was conducted, with encouraging preliminary results. These data suggest that a therapeutic approach using local injections of the combination described in this work might contribute to boost the efficacy of various cancer immunotherapy modalities. Relief of intratumor immunosuppression may increase considerably the fraction of patients who respond to vaccination directed against tumor antigens recognized by T cells.
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Bourdeaux, C. (2016). Local immunostimulation leading to rejection of accepted male skin grafts by female mice as a model for cancer immunotherapy. https://hdl.handle.net/2078.5/185188