Homeostatic T Cell Expansion to Induce Anti-Tumor Autoimmunity in Breast Cancer

摘要

We have previously shown that effective anti-tumor autoimmunity can be induced if a tumor-cell challenge is given to mice undergoing homeostatic T-cell proliferation, a process dependent on signaling by self-peptide/MHC and trophic cytokines. We investigated whether this principle can be applied to mouse models of advanced breast carcinoma, and whether the anti-tumor response can be enhanced using selected T-cell subpopulations, cytokines and tumorvaccines. The results indicated that (a) homeostatic T-cell proliferation consistently elicits anti-tumor responses; (b) irradiation is more effective than Tcell depletion by antibodies in inducing anti-tumor responses mediated by homeostatic T-cell proliferation; however, irradiation (and/or the resulting lymphopenic state) may facilitate metastasis dissemination; (c) the frequency of T regulatory (Treg) cells increases during homeostatic proliferation, particularly in the presence of a growing tumor; in vivo depletion of Treg cells enhances the anti-tumor effect of homeostatic T-cell proliferation on subcutaneous breast carcinoma; (d) gamma/delta T cells, a lymphocyte subpopulation with significant anti-tumor activity, can be induced to undergo homeostatic proliferation, and this requires depletion of both alpha/beta and gamma/delta T cell compartments and availability of either IL-7 or IL-15; (e) the anti-tumor response is diminished in aged mice, and this correlates with inefficient homeostatic T-cell proliferation; this defect can however be corrected by provision of the trophic cytokine IL-7; (f) IL-7 complexed with anti-IL-7 antibodies and/or IL-2 complexed with anti-IL-2 antibodies induce T cell proliferation in both lymphopenic and non-lymphopenic mice; (g) in non- lymphopenic mice, IL-7/antibody and particularly IL-2/antibody complexes induce cytotoxic effector functions in CD8 T cells, and inhibit tumor growth, metastasis and mortality in a model of breast carcinoma.