By Christopher J. Wheeler, PhD

Age has long been known as the strongest predictor of clinical outcome in primary brain tumor (glioma) patients and dominantly influences the outcome of most human cancers. The reasons age is such a good prognostic marker for cancer have not been clear, although gliomas arising in older patients are known to be genetically distinct from their counterparts in younger patients. This has been taken as evidence that age and glioma outcome were related because of intrinsic genetic properties of tumors arising in older patients, rather than extrinsic properties of aging hosts. Because host and tumor age are always inseparable in such clinical studies, however, an influence from extrinsic host processes on glioma genetics could not be excluded.

A host property that could theoretically influence glioma progression with age is cellular immunity. A major function of cellular immunity is the elimination of damaged, infected or cancerous cells of the body. This kind of cellular immunity hinges on the activity of a specific type of immune cell, the CD8+ T cell. These T cells are made in the thymus throughout life, but the thymus experiences sudden and dramatic shrinkage called involution at adolescence, which continues for the remainder of an individual's life. When this happens, the number of CD8+ T cells produced by the thymus also dramatically decreases. Thus, aging decreases the activity of the CD8+ subpopulation of T cells, immune cells able to recognize and respond to various types proteins. It has not been clear whether or how thymus shrinkage - and anti-tumor immunity in general - affects the development or progression of cancer in people.
Alterations in the thymus by intracranial gliomas. Thymus sections from healthy (left panel) and glioma-bearing hosts (right panel) were stained with hematoxylin and eosin. Magnification= 1000x, Arrows indicate eosinophils infiltrating the thymic parenchymal tissue (cortex) in the glioma-bearing host.

Now researchers at the Maxine Dunitz Neurosurgical Institute have found that a large fraction of the CD8+ T cells just produced by the thymuses of patients with glioblastoma multiforme (GBM), the most malignant and deadly primary brain tumor, are able to recognize and respond to tumor proteins. In contrast, the fraction of "older" CD8+ T cells (those produced much earlier by the thymus) with such anti-tumor properties is much smaller. Consequently, the level of newly produced CD8+ T cells predicts both the level of anti-tumor immune activity in these patients, as well as entirely accounts for the influence of age on their prognosis and survival [1]. In related work, it was found that only the CD8+ T cells just produced by the thymus selectively accumulated within gliomas growing in animals and that the survival of older animals with gliomas was substantially lowered when CD8+ T production was specifically diminished [2]. This suggested that new CD8+ T cells are uniquely reactive to gliomas and essentially proved that shorter survival in older glioma hosts is due to lowered production of new CD8+ T cells.

This is important because efforts to treat cancer patients by vaccinating them against their tumors are aimed at boosting the type of CD8+ T cells able to react to tumor proteins. Such vaccines work well in animals with cancer, but it hasn't been clear why they aren't as effective in cancer patients. The new research findings suggest that part of this failure of human glioma vaccines is because there is a critical shortage of new CD8+ T cells in these cancer patients. In fact, after vaccination against their tumors, nearly all of the tumor-reactive immune cells in GBM patients were derived from CD8+ T cells that were recently produced by the thymus [1]. All together, this means that increasing thymus production or increasing the numbers of newly made CD8+ T cells may substantially improve the survival of GBM and perhaps other cancer patients.

This is the first demonstration that a major and dominant aspect of cancer clinical outcome is due to host immunity. In this respect, it provides renewed hope for vaccination as a viable therapeutic option for cancer patients. In addition, these findings help pinpoint the exact cellular nature of beneficial immunity in GBM patients. Efforts are currently underway to determine the exact ways newly produced CD8+ T cells differ from older CD8+ T cells, in the hope of conferring greater anti-tumor reactivity to many more T cells in glioma patients and thereby improve immune-based cancer therapies for this rapidly fatal disease.

These studies also encourage reassessing all age-dependent phenomena in glioma patient for potential immune influence. The reason this is important is because age-related phenomena are thought to control the clinical disease course in glioma. To the extent that such phenomena are due to cellular immunity, a process whose strength is increased through vaccination, they can be manipulated to improve clinical outcome. For example, age is known to influence certain tumor genetic properties in glioma patients. It is also known that tumor genetics can determine both the natural clinical course as well as the therapeutic effectiveness of gliomas. If verified, an immune influence on glioma genetics could lead to the use of immune-based therapies as a pretreatment to enhance subsequent therapies, as well as to directly enhance patient survival.

With this in mind, it was intriguing to find that clinical responsiveness to chemotherapy was also closely related to the level of new CD8+ T cells in preliminary analyses. Based on this encouraging observation, a retrospective analysis of chemotherapeutic efficacy in all de novo glioblastoma multiforme patients treated by prior therapeutic vaccination to date has been initiated. Initial findings, which include dramatic regressions of whole body tumor mass following post-vaccine chemotherapy, support the view that vaccination enhances chemotherapeutic responsiveness.
Tumor regression following post-vaccine chemotherapy. MRI brain scans of a single patient are shown following post-vaccine recurrence (large dark circle in upper left of brain; left panel) and following subsequent chemotherapy 54 days later (2 cycles Vincristine; right panel). Scans are sagittal T1-weighted images. This patient survived more than 2 years (730 days) post-diagnosis.

Finally, since the thymus and its production of new CD8+ T cells is extremely sensitive to environmental influences such as stress hormones and other steroids, irradiation and chemotherapy, in addition to factors such as ethnicity and gender, this work may help shed light on how such factors influence the incidence and survival of gliomas and other cancers. For example, emotional stress has a negative influence on cancer prognosis, which might be related to the thymus shrinkage known to be induced by glucocorticoid stress hormones in the body. Similarly, the administration of life-saving glucocorticoids to reduce brain swelling in glioma patients might be accompanied by immune-compromising side affects. The increased incidence or malignant progression of gliomas within certain populations (males, Caucasians, etc.) might also critically involve host T cell immunity.

In conclusion, these new findings open up several intriguing possibilities into the study and immune-based treatment of cancer in general, and glioma patients specifically. It will be critically important in this regard to assess relevant treatments in experimental and human clinical glioma trials, as well as to validate relevant immunological phenomena in distinct non-glioma cancer patients.

1. Wheeler CJ, Black KL, Liu G, et al: Thymic CD8+ T cell production strongly influences tumor antigen recognition and age-dependent glioma mortality. J Immunol 171:4927-4933, 2003.
2. Prins RM, Graf MR, Merchant RE, et al: Deficits in thymic function and output of recent thymic emigrant T cells during intracranial glioma progression. J Neuro-Oncol. 64:45-54, 2003.