Injection site and regulatory T cells influence durable vaccine-induced tumorimmunity to an over-expressed self tumor associated antigen.

摘要

Tumor protein D52 (D52) is constitutively expressed in healthy tissues andoverexpressed in multiple cancers, including (but not limited to) breast,prostate and ovarian carcinomas. Although the normal functions of D52 areunknown, it is clear that increased D52 expression levels not only stimulate cellproliferation and metastasis, but also correlate with poor prognosis in a subset of breast cancer patients. The murine orthologs of D52 (mD52) shares 86% identitywith its human counterpart (hD52) and mirrors hD52 expression patterns. Theforced overexpression of mD52 induces anchorage-independent growth in vitro andpromotes tumor formation as well as spontaneous metastasis in vivo. We havepreviously reported that the intramuscular administration of recombinant mD52elicits immune responses capable of rejecting a challenge with tumor cells andpreventing spontaneous metastasis only in 50% of mice. We hypothesized thatmechanisms of peripheral tolerance dampen immune responses against mD52, thuslimiting the protective effects of vaccination. To test this hypothesis, micewere depleted of CD25(+) regulatory T cells (Tregs) and subcutaneously immunized with mD52 prior to a tumor challenge. The subcutaneous immunization failed toinduce protective antitumor immunity unless accompanied by Treg depletion, which resulted in a rate of protection of 70% as compared with.