More on the immune privilege of glioblastoma

Abstract

Immunotherapeutic approaches to glioblastoma have continued to raise interest for decades now, and the neuro-oncology scientific community seems refractory to all the frustration from efforts to translate immunotherapy into effective treatments not only in mice, but also in human patients. The strong immunosuppressive signals emanating from glioblastomas have been presented repeatedly both as the rationale to use immunotherapy and as an explanation for the failure of all efforts at clinical implementation. In fact, glioblastomas have long been considered paradigmatic cancers for cancer-associated immune inhibition thought to be mediated traditionally by soluble factors such as transforming growth factor-β (1). More recently, the glioblastoma-associated expansion of regulatory T cells, which exert major immunosuppressive activity, has received increasing attention (2). In the present issue of Neuro-Oncology, Crane and coworkers from San Francisco readdress the soluble factors released by glioblastoma cells, with a particular focus on their effects on regulatory T cells. Regulatory T cells have come into focus as a major immunosuppressive T cell population that is deregulated in various types of cancer, including glioblastoma. The authors confirm an increased frequency of regulatory T cells in the tumor tissue compared with the circulation of glioblastoma patients. Among various chemokines secreted by glioblastoma cells, CCL22 induced the migration of regulatory T cells more effectively than that of conventional T cells. However, abrogation of CCL22 signaling by blockade of its receptor, CCR4, did not fully abrogate regulatory T cell migration, suggesting that factors other than CCL22 are involved. The role of transforming growth factor-β was not examined in this context. Tumor-conditioned medium had opposite effects on regulatory and conventional T cells, stimulating proliferation in the former and inhibiting it in the latter. The authors also sought to address whether glioblastomas are more likely to convert conventional T cells into regulatory T cells than to selectively expand the regulatory T cell pool. In that regard, they observed only a transient conversion to suppressive regulatory T cell phenotypes by tumor-conditioned medium as an alternative explanation for the preferential accumulation of regulatory T cells in the tumor microenvironment. The authors go on to demonstrate that apoptosis-regulatory gene expression is differentially regulated by exposure to tumor-conditioned medium. Tumor-derived factors seem to reduce bax, bak, and bim expression in regulatory T cells but induce expression of these molecules in conventional T cells. This differential impact on gene expression would predict altered survival of different T cell populations in contact with a growing glioblastoma, favouring immune escape. Finally, the authors obtained some data on the interrelation between tumor burden and regulatory T cell populations in the peripheral blood and derived the hypothesis that there may be a close correlation. Accordingly, any immunotherapeutic approach based on T cell activity would be predicted to work best in glioblastoma patients with minimal residual disease. Although this has been traditionally assumed, there had been little clinical data to support this notion. Altogether, this study advances the understanding of how the micromilieu in glioblastomas is maintained in an immunosuppressive state and supports the view that the balance between immunosuppressive and immunostimulatory signals must be altered to facilitate tumor cell recognition and attack by the immune system. The study also leaves some important question unanswered: Is CCL22 also the relevant molecule in vivo? What about other factors, notably transforming growth factor-β? What are the signalling pathways that promote a pro-apoptotic gene expression signature in conventional T cells but convert signaling into an anti-apoptotic gene expression signature in the bad T cells, the regulatory compartment? Answers to these questions will help to delineate possibly more effective strategies of immunotherapy for glioblastoma in the future. One strength of this study is the work with biological samples from glioblastoma patients and the assembly of several findings that may help to design biomarker studies to be associated with the ongoing and planned trials of immunotherapy. Hopefully, either the ongoing efforts at targeting transforming growth factor-β by antisense oligonucleotides or small molecule inhibitors, or the more advanced efforts at targeting mutant epidermal growth factor receptor by vaccination, as well as some other, more elaborate but logistically much more challenging approaches of immunotherapy will be accompanied by appropriate biomarker studies to better understand how immunotherapy is best administered and which patients are likely to gain the most benefit from these novel therapeutic strategies.