Increased aberrance of cytokine expression in plasma of patients with more advanced squamous cell carcinoma of the head and neck
Introduction
Patients with various malignancies have previously been shown to have altered immune reactivity. Patients with squamous cell carcinoma of the head and neck (HNSCC) are particularly deficient in their immune responsiveness, with unresponsiveness being shown to stimulation through CD3 [1]. Decreased T-cell blastogenic potential by HNSCC patients was indicative of reduced patient survival [2]. Immune function can be directly inhibited by tumor production of immune inhibitory factors such as prostaglandin E2 and transforming growth factor-β (TGF-β) [3], [4], [5], [6].
Tumor presence can also cause a shift from responses that are beneficial for anti-tumor reactivity to responses that are less effective. Immune responses in tumor bearers have been shown to be biased toward a Th2 cytokine profile, which prevents the anti-tumor reactivity that can be induced through Th1 responses [7]. Th1 responses include the production of interferon-γ (IFN-γ) and interleukin (IL)-2. Th2 responses are classified as those involving increased production of IL-4, IL-6 and IL-10. Primary HNSCC cultures have been shown to produce IL-4, IL-6 and granulocyte–macrophage colony-stimulating factor (GM-CSF) [8]. Once triggered, Th2 cytokine production can be further increased. For example, IL-6 can stimulate production of IL-10 by tumor cells such as human colon carcinoma cells [9]. Production of Th1 cytokines can be inhibited by IL-10, which further exacerbates the shift toward a Th2 immune profile [10], [11]. The Th2 cytokine bias in tumor bearers is a composite of cytokines that are produced not only by the tumor, but also by immune cells. For example, T-cells that infiltrate cervical cancers are skewed toward the Th2 phenotype, with increased production of IL-4 and IL-6 [7]. The Th2 bias has a biological impact in vivo. Using a mouse melanoma model, presence of tumor elicited a Th2 cytokine response and a failure in generating protective immunity to a tumor vaccine strategy [12]. However, a shift to a Th1 cytokine bias allowed for therapeutic responsiveness to tumor. In patients with non-small cell lung cancer, a reduced capacity to produce the Th1 cytokine IL-2 coincided with reduced survival [13].
While a multitude of studies have measured cytokine levels in cancer patients and animal tumor models, typically only a very limited number of cytokines has been measured in small number of patients. HNSCC patients have been shown to have profound immunological defects, but they have not been extensively studied for the impact of disease on cytokine phenotypes. In a recent study, we measured a panel of cytokines in the plasma of 101 HNSCC patients and 40 age-matched controls. The results showed a shift to a Th2 bias in the HNSCC patients that was incomplete since levels of only select Th1 cytokines were reduced. With the exception of IL-6, cytokine levels were not influenced by the extent of tumor burden. Patients with lymph node involvement had greater levels of IL-1, IL-2 and GM-CSF than did lymph node negative patients. While it would be expected that the tumor-associate alterations in cytokine profiles of HNSCC patients would be interrelated, this has not been previously assessed. The present study showed a high degree of interrelationship among levels of both Th1 and Th2 cytokines in the control population. However, the levels of cytokines in HNSCC patients were less interrelated and became more aberrant with increasing tumor burden.
Section snippets
Profile of research subjects
Peripheral blood was collected from 101 HNSCC patients in order to measure plasma cytokine levels and to determine if there were correlations in increases or decreases in Th1 or Th2 cytokines, how this was affected by tumor burden and if it differed from that seen in age-matched control patients. The age-matched controls were 40 ENT clinic patients who did not have diagnosed malignancies and whose clinical visit were due to conditions that would not alter cytokine levels (hearing aid checks or
Discussion
Tumors have been suggested to hamper anti-tumor reactivity by skewing cytokine responses to a Th2 phenotype [7]. In a prior study, we compared cytokine levels in the plasma of patients with HNSCC to levels in age-matched control subjects. HNSCC patients showed a Th2 bias since levels of IL-4, IL-6 and IL-10 were increased compared to levels in the age-matched control population. However, a complementary uniform decrease in Th1 cytokines was not observed. Levels of IFN-γ were reduced in plasma
Patients and specimens
Peripheral blood (10 ml) was collected into EDTA-containing vacutainers from HNSCC patients and from patients attending the ENT clinic, but who were not known to have malignant disease and whose clinical visit were due to conditions that would not alter cytokine levels (hearing aid checks or earwax removal). Shown in Table 1 is a summary of the characteristics of the patient populations. None of the patients had received chemotherapy or radiation therapy within 2 months prior to blood
Acknowledgements
This work was supported by the Medical Research Service of the Department of Veterans Affairs (MRIY; DMRL), and by Grants CA79768, CA78262 and CA85266 from the National Institutes of Health (MRIY). We are grateful to Mr. Nicholas Achille at the Hines VA Hospital and Loyola University for his contributions to this study.
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