Soluble IL-2Rα facilitates IL-2–mediated immune responses and predicts reduced survival in follicular B-cell non-Hodgkin lymphoma

Abstract

Elevated serum levels of the soluble form of IL-2 receptor ␣ (sIL-2R␣) have been correlated with a poor prognosis in a variety of different types of cancers. However, its biologic relevance remains unclear and controversial. In patients with follicular B-cell non-Hodgkin lymphoma (FL), we observed that serum sIL-2R␣ levels were elevated compared with controls and that elevated sIL-2R␣ levels before treatment were associated with a poor outcome. To explore the mechanism by which sIL-2R␣ may contribute to a poor prognosis in FL, we determined the effects of sIL-2R␣ on IL-2 signaling and found that the sIL-2R␣-IL-2 complex promoted T-cell differentiation toward to inhibitory T reg cells rather than T IntroductionFollicular lymphoma (FL), the second most frequent type of non-Hodgkin lymphoma (NHL), is characterized by the presence of a significant number of normal T cells in the tumor microenvironment that have a substantial impact on antitumor immunity and patient outcome. 1,2 Previous studies have shown that the type of T cell-mediated immune response, which is regulated by the cytokine milieu, influences antitumor immunity thereby impacting patient outcome in FL. [3][4][5] Recent studies have highlighted the significance of CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T (T reg ) cells in the immune response and revealed the important role of T reg cells in the regulation of antitumor immunity. In FL, intratumoral T reg cells are present in significant numbers in biopsy specimens and markedly inhibit the proliferation and cytokine or granule production of intratumoral CD4 ϩ and CD8 ϩ T cells. [6][7][8] Lymphoma B cells play an important role in skewing the balance between T reg and IL-17-secreting T helper 17 (T H 17) cells resulting in the establishment of a profoundly inhibitory tumor microenvironment. 9 IL-2, a cytokine originally identified as a T-cell growth factor, plays a key role in the development, homeostasis, and function of T reg cells. IL-2 is essential in the development of T reg cells in the thymus, [10][11][12] and in the absence of IL-2, T reg cells cannot survive or expand in the thymus or in the periphery. [13][14][15][16] Furthermore, IL-2 is directly required for T reg cell function, and in its absence, T reg cells fail to suppress T-cell proliferation. 17,18 In B-cell NHL, IL-2 promotes T reg cell and inhibits T H 17 cell development, which is one of mechanisms explaining the presence of inhibitory tumor microenvironment in this disease. 9 IL-2 exerts its effect through binding to its receptor on cell surface. IL-2 receptor (IL-2R) is composed of 3 different subunits: ␣ (p55), ␤ (p75), and ␥ (p64). The ␣ chain binds IL-2 with low affinity and is unable to initiate a signal in the absence of the other 2 subunits confirming that the integration of receptors for IL-2 signaling is essential. In addition to membrane receptors, several studies have demonstrated the existence of truncated, soluble form of IL-2R␣ that is generated exclusively by the proteolytic cleavage of membrane IL-2R␣. 19 It has been found t...

Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma

“…9 It has been proposed as a surrogate marker for tumor progression in FL and predicts reduced survival. 9,46 Elevated soluble IL-2R expression has also been reported in several infectious and autoimmune conditions, which are known risk factors for lymphoma development and correlates with tumor bulk in intestinal lymphomas.…”

“…9 It has been proposed as a surrogate marker for tumor progression in FL and predicts reduced survival. 9,46 Elevated soluble IL-2R expression has also been reported in several infectious and autoimmune conditions, which are known risk factors for lymphoma development and correlates with tumor bulk in intestinal lymphomas. [47][48][49][50] CXCL9 is an inflammatory chemokine released by perivascular macrophages in response to IFN-g and causes the accumulation of CD81 T cells in lymphoma.…”

“…[8][9][10][11] They play a vital role in cellular differentiation, suppression, expansion, tumorigenesis, and host response to malignancy. [12][13][14][15][16] Increased levels of these immunologic receptors and ligands may be reflective of the activity of malignant cells, the tumor microenvironment, as well as the systemic host immune response.…”

Soluble Interleukin 2 Receptor-Alpha (sIL-2Rα) in the Peripheral Blood of Dogs—Comparison of Malignant Neoplasia with Other Diseases

“…In 2011 a study was made to find prognostic factors for B-cell lymphoma in humans. Increased serum levels of sIL-2Rα were determined as very important prognostic factors for this disease [9].…”

Diagnostic value of soluble interleukin-2 receptor in patients with lymphoproliferative diseases

“…В част-ности, увеличение сывороточного уровня sIL-2R служит диагностическим признаком гиперпролиферации лимфо-цитов при гемобластозах и является показателем неблаго-приятного прогноза течения опухолевого процесса [1,2,[14][15][16][17]. Кроме того, sIL-2R является неспецифическим маркером воспаления [14][15][16].…”