Mechanisms of malignant glioma immune resistance and sources of immunosuppression

Abstract

High grade malignant gliomas are genetically unstable, heterogeneous and highly infiltrative; all characteristics that lend glioma cells superior advantages in resisting conventional therapies. Unfortunately, the median survival time for patients with glioblastoma multiforme remains discouraging at 12-15 months from diagnosis. Neuroimmunologists/oncologists have focused their research efforts to harness the power of the immune system to improve brain tumor patient survival. In the past 30 years, small numbers of patients have been enrolled in a plethora of experimental immunotherapy Phase I and II trials. Some remarkable anecdotal responses to immune therapy are evident. Yet, the reasons for the mixed responses remain an enigma. The inability of the devised immunotherapies to consistently increase survival may be due, in part, to intrinsically-resistant glioma cells. It is also probable that the tumor compartment of the tumor-bearing host has mechanisms or produces factors that promote tumor tolerance and immune suppression. Finally, with adoptive immunotherapy of ex vivo activated effector cell preparations, the existence of suppressor T cells within them theoretically may contribute to immunotherapeutic failure. In this review, we will summarize our own studies with immunotherapy resistant glioma cell models, as well as cover other examined immunosuppressive factors in the tumor microenvironment and immune effector cell suppressor populations that may contribute to the overall immune suppression. An in-depth understanding of the obstacles will be necessary to appropriately develop strategies to overcome the resistance and improve survival in this select population of cancer patients.

Figures

Figure 1

Depiction of normal class I HLA presentation and other aberrant HLA phenotypic defects in tumors. (A) Normal HLA class I allele presentation is shown on a tumor cell. The heavy HLA class I α chains associate with the invariant β2-m chain (black circle) and antigenic peptide (open circle) at the plasma membrane surface. (B) Loss of HLA antigen expression at the tumor cell surface is shown. Inactivating mutations of the β2-m genes may prevent β2-m expression, leading to a total loss of HLA class I. (C) Specific HLA allelic dropout is demonstrated. In this instance we show HLA class I A allelic downregulation that decreases the number of HLA/peptide complexes at the cell surface. (D) HLA haplotype loss is shown. As a result of loss of portions of chromosome 6, a complete loss of maternal or paternal HLA would be displayed as a HLA class I downregulation that would more drastically decrease the number of HLA/peptide complexes at the cell surface than what is depicted in C.

Figure 2

Disruption of Fas-induced apoptosis or upregulation of FasL may provide tumor cell protection to T lymphocyte induced cell injury. Decreased Fas expression by the glioma cells or their secretion of the FasL decoy receptor, DcR3, can inhibit death receptor induced apoptosis. The transduction of apoptotic signals by way of the Fas receptor is inhibited when tumor cells express cFLIP or IAPs. The cFLIP protein inhibits caspase 8 activity. The IAP family members suppress caspase 3 and caspase 9 activity. Tumor cells may counterattack T cells by expressing FasL, which can engage Fas on the T cell plasma membrane to initiate T cell apoptosis.

German G. Gomez and Carol A. Kruse