Abstract 3542: Interplay between cancer and the immune system: Beneficial role of TILs and mechanisms of tumor immune escape in GBM patients
Authors: Kmiecik Justyna , Poli Aurélie , Brons Nicolaas H. C. , Zimmer Jacques , Chekenya Martha 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most malignant brain cancer and despite advances in present treatment regimen, the patients’ survival remains low, emphasizing importance of continued research to develop novel therapies. One of the promising treatment strategies is immunotherapy. However, detailed studies of the immune status of GBM patients are required to design appropriate immunotherapy tailored to these patients. Our preliminary characterization of 63 GBM patients’ biopsies using IHC staining for CD3, CD4 and CD8 markers revealed a great heterogeneity in the amounts of T-cell infiltrates between and within the patients’ tumors. The amounts of CD3+, CD4+ and CD8+ T-cells were quantified and correlated with patients’ survival outcomes. Reduced CD3+ T-cell infiltration into the tumor (&lt;5%) was associated with shorter median survival of 7 months compared to 12 months in the patients with &gt;5% T-cells (p=0.0029). Similarly, significant (p=0.0062) positive correlation of the level of CD8+ cells infiltration with longer patients’ survival was observed. In further studies we focused on detailed characterization of tumor infiltrating and peripheral blood lymphocytes and based on these results we propose several mechanisms impairing the patients’ immune system. Within the tumor microenvironment immunosuppression is driven by increased expression of CD39 and CD73 molecules that leads to high levels of extracellular adenosine resulting in T-cell suppression. Additionally, we observed modulation of Fas expression on tumor cells and FasL concentration in patients’ plasma dependent on the immune cells’ status. This may result in either tumor's escape from Fas-mediated cytotoxicity or apoptosis of the immune cells. A subpopulation of the patients had elevated CD8+ regulatory T-cells that are known to suppress APCs - a major immune cell population infiltrating the tumor. However, in contrast to other published reports, we didn't detect CD4+ Tregs among TILs. In addition, we demonstrated a systemic immunosuppression due to decreased numbers of T-helper cells in the peripheral blood compared to healthy donors (p=0.0391) and their up-regulated expression of the inhibitory receptor CD152 (p=0.0039). Moreover, increased concentration of IL-10 (p=0.0039) and decreased concentration of IL-2 and IL-12 in patients’ plasma comparing to healthy donors’ indicates that the immune response balance is shifted towards Th2 anti-inflammatory response.In conclusion, our preliminary results showing that the increased T-cells infiltration to the tumor correlates with patients’ longer survival, suggest that there is a potential for developing immunotherapies against GBM. However, further studies revealed a large repertoire of immunosuppressive mechanisms developed by the tumor that need to be taken into consideration when designing an immunotherapy tailored to GBM patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3542. doi:1538-7445.AM2012-3542