Immune-mediated serum changes that can be identified more than 2 decades before a brain tumor is diagnosed could offer new hope for early intervention.
The findings are at an early stage and need to be confirmed, but they may eventually "inform clinical practice," says lead investigator Judith Schwartzbaum, PhD, associate professor of epidemiology at the Ohio State University College of Public Health and Comprehensive Cancer Center in Columbus.
The study evaluated 277 prediagnostic serum cytokines — the signaling proteins that regulate immune responses — and their association with glioma. The researchers found that five serum cytokines and a cytokine-soluble receptor interaction are all independently associated with changes in the preclinical risk for brain cancer.
Soluble interleukin 10 receptor beta, vascular endothelial growth factor (VEGF), catenin beta-1 (beta-catenin), and C-C motif chemokine 22 (CCL22) are cytokines related to glioma risk (P ≤.05) more than 10 years before diagnosis, the researchers say in an article published online June 8 in PLOS ONE.
The odds ratio (OR) was 1.53 for CCL22 among participants whose blood was drawn more than 20 years before they were diagnosed with glioma. A one unit increase in the standardized log of cytokine levels was associated with a 53% increase in the odds of glioma.
In addition, leukemia inhibitory factor was associated with decreased glioma risk in the 5-year period prior to glioma diagnosis (OR, 0.47). After adjustment, the interaction between soluble interleukin 4 receptor alpha sIL4 and interleukin 4 receptor alpha (sIL4RA) persisted for more than 20 years before diagnosis (OR = 1.72).
Previously Unknown Changes
Currently, the median survival time after diagnosis of glioblastoma is 14 months. Preclinical symptoms occur 3 to 6 months before diagnosis of stage 4 glioma or glioblastoma in about 80% of adult brain cancers, the authors note.
The primary contribution of this study "is that it further describes previously unknown prediagnostic cytokine changes," Dr Schwartzbaum and colleagues comment, adding that "we suggest caution in their interpretation."
Overall, only seven ORs were significantly associated with glioma (0.5%), and two cytokines were eliminated, they point out. To achieve credibility, the OR findings must be replicated in another data set. Preclinical studies of additional immune function biomarkers, including immune function cells, "should be conducted with the ultimate goal of identifying signs of gliomagenesis in its earliest stages," the authors emphasize. "Our cytokine interaction term and correlation results better represent the known biological interactions among cytokines."
Our initial findings must be replicated. Dr Judith Schwartzbaum
"Our initial findings must be replicated," Dr Schwartzbaum confirmed in an email. "We need to look at other immune constituents of peripheral circulation in humans before glioma diagnosis." Whether the patterns are unique to glioma or occur with other tumors also needs to be determined, she said.
The findings cannot be used to screen patients for glioma, but "understanding the process of gliomagenesis may lead to findings that inform clinical practice, " Dr Schwartzbaum acknowledged. "If our findings can be verified, they may eventually be used in combination with imaging or with other glioma indicators — for example, with genetic or epigenetic markers of glioma."
Analysis of Blood Samples
For the study, the researchers analyzed serum samples from 487 blood donors who were subsequently diagnosed with glioma. The samples were compared to the same number of control specimens from individuals matched for age, date of blood collection, and sex. All samples came from the Janus Serum Bank Cohort in Oslo, Norway. The biobank, which is now linked to the Norwegian Cancer Registry, has 300,000 serum samples from healthy individuals, most of whom were participating in routine cardiovascular health examinations conducted by the National Health Screening Services since 1972.
The researchers used heat maps to compare the interaction of 12 cytokines between the microenvironment and the tumor in both cases and controls. This was also performed in all 277 cytokines in the data set.
In the glioma microenvironment, cytokines are appropriated by the tumor and assist in immune suppression and tumor invasion, the researchers explain. Angiogenic growth factor provides the tumor with a blood supply; other immunosuppressive cytokines recruit regulatory T cells and facilitate growth of brain tumor initiating cells.
The study authors could not determine the within-person effects of time to diagnosis on peripheral cytokine levels and correlations. The levels of time before diagnosis were similar between control patients and glioma patients except for those within 5 years of diagnosis. This suggests the findings cannot be attributed to differences over time in study participants, they say.
Among the 12 cytokines, correlations were weaker among glioma patients than among control patients, a finding consistent with results from their earlier studyshowing changes in allergy-related cytokine activity up to 5 years before a brain tumor diagnosis. In that study, an interaction between interleukin 4, a cytokine active in allergy and normal brain function, and its soluble receptor, sIL4RA, appeared to reduce glioma risk.
In the current study, the researchers had expected to see a similar pattern, with control patients having higher levels of allergy-related cytokines than patients who subsequently developed glioma. When that did not happen, they expected to find elevations in the levels of inflammatory or immunosuppressive cytokines consistent with studies of glioma patients after diagnosis. That was not the case either. Instead, they observed that cytokines known to play a role in gliomagenesis, such as VEGF1, CCL222, and beta-catenin-3, were associated with future cases of glioma more than 10 years before diagnosis.
"That really surprised us," Dr Schwartzbaum told Medscape Medical News. "We expected to find varying levels of each cytokine independent of the other cytokines. Obviously, cytokines have other roles besides those in glioma progression. However, the reason that future cases but not controls have higher levels of these cytokines long before diagnosis is not known. They may increase the glioma risk."
This finding is also consistent with research showing bidirectional communication between the brain and systemic immunity in the absence of pathology, she said. The research group that conducted that study reported that a lymphatic system in the meninges transports immune cells to the cervical lymph nodes and concluded that the role of systemic immunity in cancer immunotherapy has been underestimated. "We would add that its role has probably not been appreciated in gliomagenesis either," Dr Schwartzbaum said.
Funding for this study was provided by the National Cancer Institute of the National Institutes of Health. Coauthor Ruo-Pan Huang, MD, PhD, is employed by RayBiotech, Inc. The other authors have disclosed no relevant financial relationships.
PLoS One. Published on June 8, 2017. Full text