Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response

Abstract

A major barrier to successful antitumor vaccination is tolerance of high-avidity T cells specific to tumor antigens. In keeping with this notion, HER-2/neu (neu)-targeted vaccines, which raise strong CD8+ T cell responses to a dominant peptide (RNEU420-429) in WT FVB/N mice and protect them from a neu-expressing tumor challenge, fail to do so in MMTV-neu (neu-N) transgenic mice. However, treatment of neu-N mice with vaccine and cyclophosphamide-containing chemotherapy resulted in tumor protection in a proportion of mice. This effect was specifically abrogated by the transfer of neu-N–derived CD4+CD25+ T cells. RNEU420-429-specific CD8+ T cells were identified only in neu-N mice given vaccine and cyclophosphamide chemotherapy which rejected tumor challenge. Tetramer-binding studies demonstrated that cyclophosphamide pretreatment allowed the activation of high-avidity RNEU420-429-specific CD8+ T cells comparable to those generated from vaccinated FVB/N mice. Cyclophosphamide seemed to inhibit regulatory T (T reg) cells by selectively depleting the cycling population of CD4+CD25+ T cells in neu-N mice. These findings demonstrate that neu-N mice possess latent pools of high-avidity neu-specific CD8+ T cells that can be recruited to produce an effective antitumor response if T reg cells are blocked or removed by using approaches such as administration of cyclophosphamide before vaccination.

Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatorycells

“…The heightened vaccine-based antitumor immune response in irradiated hosts was associated with tumor regression and prolonged survival of mice. It had previously been thought that some cytotoxic agents, such as cyclophosphamide, might enhance the efficacy of adoptively transferred immunotherapy by augmenting the engraftment of adoptively transferred tumor-reactive effector T cells, [11][12][13] possibly by creating space. 1, 14 However, in our study, vaccination after irradiation without adoptive transfer yielded similar results, indicating that a self-reconstituted host immune system is reliable for antigen stimulation.…”

Alphaviral vector-transduced dendritic cells are successful therapeutic vaccines against neu-overexpressing tumors in wild-type mice

“…Cells were washed and suspended in 0.5% formaldehyde prior to analysis. Quantification of CD8 + T cells specific for RNEU [420][421][422][423][424][425][426][427][428][429] was performed by intracellular IFN-γ staining as previously described [20].…”

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

“…60,73,74 Paclitaxel PTX is a mitotic inhibitor that causes cell cycle arrest by stabilizing tubulin in microtubules. It is another useful agent for LDM therapy given its broad spectrum antitumor activity and ability to in vitro inhibit endothelial cell functions that are fundamental for angiogenesis.…”