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Cancer statistics show a disproportionately higher burden of tumors in the old. Most of the studies evaluating vaccination strategies have not taken into consideration the effect that aging has on the immune system. For the first time, we describe an animal tumor model in which self-tolerance and aging are present at the same time. FVB-Her-2/neu mice which are tolerant to neu antigens crossed with HLA-A2/Kb mice (A2xneu) develop spontaneous tumors when they are more than 22 months old. Analysis of CD8+ T-cell–specific responses in A2xneu mice indicated that the priming activity of old A2xneu mice to induce an immune response was diminished compared with young animals. Following intratumoral injections of CpG-ODN, ∼30% of young A2xneu mice rejected the tumor; however, no antitumor effect was observed in old A2xneu mice. Analysis of T regulatory cells (Treg) indicated that there are significantly more Tregs in old animals. After CpG-ODN vaccination plus Treg depletion, 70% of young A2xneu mice rejected the tumor. The same treatment prolonged survival in old A2xneu mice, but none of the animals rejected the tumor. Even though CpG-ODN injections plus Treg depletion could rescue the antitumor responses against self-tumor antigens in young tolerant mice, the same therapy is not as effective in old tolerant hosts. Relevant tumor models such as the A2xneu mice in which self-tolerance and aging are present at the same time are critical to allow the optimization of vaccination strategies to effectively stimulate immune responses against self-tumor antigens in the young and the old. [Cancer Res 2008;68(13):5423–31]

Immune responses against cancer rely upon leukocyte trafficking patterns that are coordinated by chemokines. CCR5, the receptor for chemotactic chemokines MIP1alpha, MIP1beta, and RANTES (CCL3, CCL4, CCL5), exerts major regulatory effects on CD4+- and CD8+ T cell-mediated immunity. Although CCR5 and its ligands participate in the response to various pathogens, its relevance to tumoral immune control has been debated. Here, we report that CCR5 has a specific, ligand-dependent role in optimizing antitumor responses. In adoptive transfer studies, efficient tumor rejection required CCR5 expression by both CD4+ and CD8+ T cells. CCR5 activation in CD4+ cells resulted in CD40L upregulation, leading to full maturation of antigen-presenting cells and enhanced CD8+ T-cell crosspriming and tumor infiltration. CCR5 reduced chemical-induced fibrosarcoma incidence and growth, but did not affect the onset or progression of spontaneous breast cancers in tolerogenic Tg(MMTV-neu) mice. However, CCR5 was required for TLR9-mediated reactivation of antineu responses in these mice. Our results indicate that CCR5 boosts T-cell responses to tumors by modulating helper-dependent CD8+ T-cell activation. Cancer Res; 71(16); 5455–66. ©2011 AACR.

Immunotherapy is an attractive strategy for cancer treatment. However, self-tolerance is one of the major mechanisms that dampen immune responses against self-tumor antigens. We have demonstrated that Her-2/neu transgenic mice (neu mice) are tolerant to neu antigens and contain only a low avidity repertoire for neu. However, this repertoire has antitumor activity. Immunizations of neu mice are capable of activating the low-avidity T cells that, at best, retard the tumor growth. To increase the efficacy of the antitumor responses in neu mice, we hypothesized that immunotherapy in combination with antiangiogenic therapy would be a more efficient strategy for tumor eradication. The rationale for using this combination was that by decreasing the growth rate of the tumor with an antiangiogenic therapy, the low-avidity repertoire of neu mice stimulated by immunotherapeutic intervention would be more effective in destroying the slow growing tumor. To test this hypothesis, we stably expressed a soluble form of the Flt-1 vascular endothelial growth factor receptor (sFlt-1) on N202.1A cells, using a retrovirus vector. Expression of sFlt-1 on N202.1A (N202-Flt) cells significantly inhibited the tumor growth compared with N202.1A parental cells. In contrast to the application of immunotherapy alone or antiangiogenic therapy alone, which delayed the tumor growth, the combination of the two therapies provided complete inhibition of tumor growth in Her-2/neu mice. These results indicate that the use of tumor targeting with immunotherapy in simultaneous combination with antiangiogenic therapy provides a more efficient strategy for the treatment of solid tumors.