Gene Ther Mol Biol Vol 10, 133-146,
2006
Mechanisms
of malignant glioma immune resistance and sources of
immunosuppression
German G.
Gomez1 and Carol A. Kruse2,*
1Department of
Pathology, University of Colorado Health Sciences Center,
Denver, CO 80262, USA
2Division of Cancer
Biology and Brain Tumor Research Program, La Jolla Institute for Molecular
Medicine, San Diego, CA 92121, USA
__________________________________________________________________________________
*Correspondence: Carol A. Kruse, Ph.D, Professor of Cancer Biology, The La Jolla
Institute for Molecular Medicine, 4570 Executive Drive, Suite 100, San Diego,
CA 92121; Tel: 858-587-8788 ext 142; Fax: 858-587-6742; e-mail:
ckruse@ljimm.org
Key
words: T regulatory cells,
cellular immunotherapy,
immunotherapy, brain tumors, CTL resistance, effector T lymphocytes,
FasL, immunosuppressive
mechanisms, apoptosis, adhesion molecules, extracellular matrix
proteins, cytokines
Abbreviations: alloreactive cytotoxic T lymphocytes, (aCTL); antigen presenting cells,
(APC); blood brain barrier, (BBB); central nervous system, (CNS);
cyclooxygenase, (COX); dendritic cells, (DCs); extracellular matrix, (ECM);
Fas-associated death domain-like IL-1b-converting enzyme inhibitory protein c,
(cFLIP); Glioblastoma multiforme, (GBM); Glioma associated antigens, (GAA);
Human leukocyte antigens, (HLA); Immunotherapy resistant, (ITR); Indoleamine
2,3-dioxygenase, (IDO); Inhibitors of apoptosis proteins, (IAP); Interferon,
(IFN); Interleukin, (IL); Intercellular adhesion molecule-1, (ICAM-1); Killer
immunoglobulin-like receptors, (KIRs); Leukocyte function antigen-1, (LFA-1);
Major histocompatibility complex, (MHC); MHC class I-related, (MIC); Mixed
lymphocyte reaction, (MLR); Natural killer, (NK); Peripheral blood mononuclear cells (PBMNC);
Prostaglandin E2, (PGE2); Signal transducer and
activator of transcription-3 (STAT-3); T cell receptor, (TCR); T helper, (Th);
T regulatory cell, (Treg); Transforming growth factor, (TGF); Tumor associated
antigens, (TAA); Tumor infiltrating lymphocytes, (TIL); Tumor necrosis factor,
(TNF)
Summary
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.
I. Introduction
The majority of primary tumors of the central nervous
system (CNS) are of astrocytic lineage (CBTRUS, 2005). Of the astrocytomas, the most malignant form,
glioblastoma multiforme (GBM), is diagnosed at a much higher frequency than
lower grade astrocytomas. The median survival time for GBM patients is poor,
approximating 12-15 months even with aggressive upfront treatment
(Stupp et al, 2005). Several obstacles prevent the complete eradication
of GBM by conventional therapies. GBMs locally but diffusely infiltrate
neighboring brain tissue through white matter tracts, perivascular, and
periventricular spaces, and often invading cells are found centimeters away
from the primary tumor mass (Hochberg and Pruitt, 1980). As a consequence, GBM patients are rarely cured of
their tumors by surgical intervention. The significant degree of genetic
instability (Louis and Gusella, 1995) and cellular heterogeneity within GBM ensures that
not all cellular variants will respond to radiation or chemotherapy. For
example, glioblastoma cells downregulate p53 (Shu et al, 1998) or upregulate DNA repair enzymes such as
O6-methylguanine-DNA
methyltransferase (Bandres et al, 2005) as a means to avoid radiation and chemotherapy
induced-cell death, respectively. In addition, the physical isolation of brain
tumors by the blood–brain barrier (BBB) and drug efflux pumps integrated
into the membranes of endothelial cells at the BBB interface prevents efficient
delivery of systemically administered chemotherapeutic agents
(Doolittle et al, 2005).
To circumvent these limitations, researchers have tried to make the tumor cells more visible to the immune system (Paul and Kruse, 2001). To date, knowledge of the complex coordination of anti-tumor immune responses within the brain remains limited. Often translation of brain tumor immunotherapies is partially based upon knowledge of anti-tumor immune responses from tissues outside the brain or in xenograft models with defective endogenous immune compartments. Despite these restrictions, promising results have been observed in brain tumor patients treated with a variety of immunotherapeutic approaches