Treg infiltration in glioma: a hurdle for antiglioma immunotherapy

Immunotherapy is an emerging treatment strategy for glioblastoma multiforme (GBM) [1,2]. Although promising results are available, the estimated clinical success rate that was aimed for with this highly selective technology has not yet been realized. Many factors work in concert to inhibit antiglioma immunity, including immunosuppressive cytokines and impaired APC function. Tregs have shown to play a critical role in suppressing the antitumor immune responses in GBM patients [3]. Within the scope of glial tumors, Tregs have the highest predilection for tumors of the astrocytic lineage and specifically in the high-grade gliomas, such as GBM [4]. Current research on Tregs infiltrating GBM is led by two critical issues. What is the prognostic relevance of intratumoral Treg accumulation in GBM patients and what are the mechanisms contributing to this phenomenon? A subgroup analysis in a group of 29 patients with GBM showed a moderate, not significantly inverted association between Tregs (CD4⁺ FoxP3⁺ CD25^high CD127^low ) and survival [5]. This finding emphasizes the redundancy of the immunosuppressive mechanisms at play in GBM. Moreover, this study did not take the prognostic relevance of systemic Tregs into account. Regarding how Tregs enrich in tumors, there are several nonmutually exclusive possibilities [6]. Tregs recognize the large amount of self-antigens provided by proliferating and dying tumor cells and, hence, become recruited. Moreover, Tregs are preferentially attracted by tumor-derived chemokines. It is also probable that Tregs are induced from non-Tregs owing to high concentrations of TGF-βsecreted by tumor cells and/or dendritic cells present in tumors. In the context of GBM, there is a preferential deposition of Tregs in the tumor microenvironment rather than in the peripheral blood, suggesting the presence of chemotactic factors [4]. Indeed, Jordan et al. showed that Treg migration towards gliomas is mediated by the glioma-secreted chemokines CCL2 and CCL22 [7]. Concordant with this finding, Jacobs et al. found that Tregs in GBM, in contrast to other tumor-infiltrating effector lymphocytes, highly express the CCL22 receptor CCR4 [5]. In order to tackle the Treg compartment in GBM patients it is of high importance to identify which other mechanisms, in addition to preferential tumor-induced chemoattraction, can contribute to the overrepresentation of Tregs in the tumor area compared with the systemic compartment.

Summary of methods & results

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