The Clinical Significance of Cytokines and Soluble Forms of Membrane-Derived Activation Antigens in the Serum of Patients with Hodgkin's Disease

Abstract

In a search for specific serum markers with prognostic impact in Hodgkin's Disease (HD), we evaluated the clinical significance of several cytokines (IL-1 beta, IL-2, IL-3, IL-6, G-CSF, GM-CSF, TNF-alpha) and soluble forms of membrane-derived antigens (sCD4, sCD8, sCD23, sCD25, sCD30) in the serum of patients with untreated HD. Elevations of three groups of serum factors were observed: Firstly, elevations of the hematopoietic cytokines GM-CSF (detected in 39%), IL-6 (57%) and IL-3 (13%), which occurred simultaneously in the majority of the cases; secondly, simultaneous elevations of the inflammatory cytokines TNF-alpha and IL-1 beta (detected in 7%); and finally, elevations of membrane-derived activation antigens sCD8, sCD25, and sCD30. While the cytokine levels did not correlate with other obvious parameters, the membrane-derived activation antigens sCD8, sCD25 and sCD30 were associated with a poor prognosis. Only sCD30 correlated with disease activity and holds promise for the follow-up of patients in remission. Further investigations of these parameters at the cellular level might help to elucidate the enigmatic biology of HD.

Biologic features of Hodgkin lymphoma and the development of biologic prognostic factors in Hodgkin lymphoma: Tumor and microenvironment

“…It can be detected in serum of HL patients and sCD30 is one of the most studied serum markers in cHL. Elevated levels have been shown to be associated with adverse outcome in several studies [63][64][65][66][67][68][69][70]. In the largest series to date, Visco et al and Casanovas et al evaluated sCD30 in 321 and 519 newly diagnosed patients, respectively.…”

Prognostic Biomarkers for Hodgkin Lymphoma

“…Higher levels of TNF have been observed in adult and pediatric HL patients compared with healthy controls [41][42][43][44][45][46]. This phenomenon is not specific for HL but was also observed in other lymphoma and leukemia patients [42,43,47].…”

“…TNF-like cytokines have also been described in other arthropods, nematodes, and mollusks [37][38][39], but their function in these organisms has not yet been characterized. In mammals, TNF (like other members of this family) has several immune-regulatory functions and (in addition to direct effects on tumor cells) the proinflammatory activities of TNF can augment antitumor immune responses [34,40].Higher levels of TNF have been observed in adult and pediatric HL patients compared with healthy controls [41][42][43][44][45][46]. This phenomenon is not specific for HL but was also observed in other lymphoma and leukemia patients [42,43,47].…”

“…A possible reason for the difference between RTA conjugates and MMAE conjugates might be the fact that the unconjugated small MMAE is highly toxic, whereas unconjugated RTA is toxic only after entering the cytoplasm, and the large ribosome inactivating protein RTA cannot cross the cell membrane (in ricin the B-chain is responsible for uptake). CD30 is released from the cell surface by ectodomain shedding [101], and increased levels of soluble CD30 (sCD30) have repeatedly been identified as unfavorable prognostic factor [41,45,46,[102][103][104][105][106][107][108][109]. Elevated levels of sCD30 might reflect higher tumor burden and/or stronger activation of bystander cells.…”

“…In multivariate analysis, however, TNF was not an independent factor. In other studies, no significant correlation between TNF levels and survival was detected [41,46]. Interestingly, TNF can act as growth factor for normal cells and tumor cells [50][51][52], but this has not been described for HL cells.…”