Since tumor-associated antigens are primarily encoded by normal unmutated genes, the immune responses elicited by an effective cancer immunotherapy are essentially autoimmune in nature. However, breaking tolerance for self-antigens remains a major challenge. Recent studies showed that, under lymphopenic conditions, peripheral T cells proliferate to re-establish appropriate cell numbers. Such homeostatic T cell proliferation depends on recognition of self-peptide/MHC ligands and is accompanied by acquisition of several activation markers and effector functions, including cytotoxicity. On this basis, we hypothesized that induction of homeostatic T cell proliferation concurrent with tumor cell challenge may be a way to preferentially expand and activate otherwise tolerant lymphocytes and, hence, elicit effective anti-tumor autoimmunity. Our preliminary experiments with melanoma cell-challenged lymphopenic mice transferred with small numbers of syngeneic T cells indicated that this is indeed the case. Here, we wish to extend this novel observation by examining the clinical applicability, particularly the mechanistic basis of this approach.
Specific Aims i nclude (a) defining the efficacy of homeostatic T cell proliferation on established tumors at different disease stages; (b) exploring the role of direct presentation by tumor cells versus cross-presentation by antigen-presenting cells during T cell homeostatic expansion and priming; (c) evaluating mechanisms of T cell selection and break of tolerance for tumor antigens; and (d) determining whether the anti-tumor effect can be improved by supplementing trophic cytokines that promote homeostatic T cell proliferation and survival, and enhance maintenance of memory T cells. The results will define the role of homeostatic T cell proliferation in tumor autoimmunity, and provide new approaches to the treatment of cancer. ? ?
| Gonzalez-Quintial, Rosana; Lawson, Brian R; Scatizzi, John C et al. (2011) Systemic autoimmunity and lymphoproliferation are associated with excess IL-7 and inhibited by IL-7R? blockade. PLoS One 6:e27528 |
