Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate‐pulsed dendritic cells in a murine glioma model

Abstract

Both melanoma and glioma cells are of neuroectodermal origin and share common tumor associated antigens. In this article, we report that the melanocyte differentiation antigen TRP2 (tyrosinase-related protein 2) is not predominately involved in the tumor rejection of a syngeneic murine glioma. Although GL261 glioma cells endogenously expressed TRP2 and were lysed by TRP2 specific cytotoxic T cells (CTLs) in vitro, vaccinations with TRP2 peptide-pulsed dendritic cells (DCs) could only induce minor antiglioma responses in a prophylactic setting and failed to work in a stringent setting where vaccine and tumor were administered on the same day. Further analysis revealed that TRP2 is not recognized by bulk CTLs after depletion of regulatory T cells which results in tumor rejections in vivo. In contrast to TRP2 peptidepulsed DC, tumor lysate-pulsed DCs were more potent as a vaccine and completely protected mice from tumor outgrowth in a prophylactic setting. However, the vaccine efficacy of tumor lysate-pulsed DC was not sufficient to prevent the tumor outgrowth when tumors were inoculated the same day. In this case, Treg depletion before vaccination was essential to boost antiglioma immune responses leading to the rejection of 80% of the mice and long-term immunity. Therefore, we conclude that counteracting the immunosuppressive glioma tumor environment via depletion of regulatory T cells is a prerequisite for successful eradication of gliomas after targeting multiple tumor antigens by using tumor lysate-pulsed DCs as a vaccine in a more stringent setting. ' 2007 Wiley-Liss, Inc.Key words: glioma; TRP2; tumor lysate; dendritic cell; regulatory T cell; CD25-depletion Dendritic cell (DC)-based immunotherapy is regarded as an attractive strategy for the therapy of malignant gliomas. Several animal studies have demonstrated that DCs can efficiently mediate the induction of antitumor responses within the central nervous system. 1-9 A number of phase I/II studies have been performed and others are ongoing to evaluate and improve DC vaccines for patients with malignant gliomas. 10-15Although DC-based immunotherapies for various cancers including malignant gliomas led to the induction of antitumor cytotoxic T cells (CTLs) and lymphocyte infiltration into tumors in situ, objective tumor regressions have been limited to a few cases. 16 In addition, most mouse glioma models primarily assessed the ability of DC-based immunotherapy to prevent the outgrowth of tumor in a prophylactic setting in which tumor cells are injected after vaccination. Attempts to treat tumors at more stringent conditions, like administration of tumor cells and vaccine on the same day (simultaneous setting) or a therapeutic setting were either not evaluated or shown to be unsuccessful, despite the presence of large numbers of antiglioma immune cells.A major obstacle for an active immunization against solid tumors is the presence of immunosuppressive factors at the local tumor environment. There is accumulating evidence that active suppressor mechanisms ar...

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

“…A single intratumoral injection of CpG-ODN was sufficient to induce Teff associated glioma eradication and to induce protective antitumor immunity. The potency of local TLR treatment of gliomas is further underlined by our observation that the activation of the immune system using this approach is far more effective in a therapeutic setting than repeated peripheral vaccinations with tumor lysate-loaded DC (62). Therefore, it will be interesting to explore the local delivery of TLR ligands as an immunotherapeutic strategy to break local immune suppression in glioma patients.…”

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

“…Breaking peripheral tolerance by depletion of Tregs with anti-CD25 antibodies, thereby targeting the a-chain of the IL2 receptor, has demonstrated an improved immune-mediated tumor rejection in murine models (66). Unfortunately, in humans, anti-CD25 antibodies did not enhance the efficacy of DC vaccination in multiple tumor types, despite efficient depletion of Tregs from the peripheral circulation and increased tumor-specific T-cell frequencies (67,68).…”

Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

“…32 Multiple mechanisms have been defined to be responsible for the suppression, including secretion of transforming growth factor-␤ 33,34 and IL-10, 33,34 as well as inhibition of dendritic cell (DC) maturation. 33,35 Despite the great potential for Treg depletion in cancer therapies, the efficacy has been limited to prophylactic settings where depletion of Tregs is given before the establishment of tumor. 36,37 The present studies were undertaken to determine whether endogenous Tregs present at the site of AML dissemination constrained the antileukemia efficacy of anti-AML CTL adoptive transfer in a rodent model as a prelude to future clinical trials.…”