No abstract

BLyS, recently shown to be critical for survival of normal B cells, has been found to be elevated in a number of immune disease models. A role for BLyS in the survival of malignant B cells has also been revealed and we therefore sought to identify a role for BLyS and its receptors in non-Hodgkin lymphoma (NHL). We found that tumor cells from all NHL histologic subtypes expressed one or more of 3 known receptors (BCMA, TACI, and BAFF-R) for BLyS; however, the pattern of expression was variable. We provide evidence that BLyS is expressed in tumors from patients with NHL and that BLyS levels increase as tumors transform to a more aggressive phenotype. Additionally, we provide evidence that serum BLyS levels are elevated in a subgroup of patients with NHL. In patients with de novo large B-cell lymphoma, a high BLyS level correlated with a poorer median overall survival, the presence of constitutional symptoms, and elevated values of lactic dehydrogenase. When BLyS levels were correlated with response to therapy in all patients, responding patients had a significantly lower BLyS level than those with progressive disease. In summary, we found that BLyS and its receptors represent a potentially important therapeutic target in B-cell lymphoma.

Key Points Alternatively polarized macrophages are abundant constituents of the tumor microenvironment in T-cell lymphoproliferative disorders. GATA-3 expression identifies a subset of PTCL, NOS with a distinct cytokine profile and inferior survival.

IntroductionIt is well established that tumor cells are able to evade detection by the host immune system and to proliferate despite immunotherapeutic strategies to inhibit them. The immune-escape mechanisms of tumors range from impaired antigen presentation and apoptosis resistance to the production of immunosuppressive factors. 1,2 Although there is commonly significant infiltration of CD4 ϩ T helper cells and CD8 ϩ cytotoxic T lymphocyte (CTL) cells at the tumor site, tumor cells can use immunosuppressive strategies to induce CD4 ϩ and CD8 ϩ T-cell anergy and create a tolerant tumor microenvironment. 2 It has been shown that antigen-presenting cells (APCs) play a crucial role in tolerizing tumor antigen-specific CD4 ϩ and CD8 ϩ T cells. 3,4 Significant interest has recently been focused on the premise that tumors may subvert tumor immunity by promoting the expansion, recruitment, and activation of regulatory T (T reg ) cells. CD4 ϩ T reg subsets include naturally occurring CD4 ϩ CD25 ϩ T reg cells as well as peripherally induced CD4 ϩ T reg cells. Naturally occurring T reg cells arise as a distinct lineage from the thymus and represent approximately 10% of peripheral CD4 ϩ T cells in mice and humans. However, T reg cells can be generated in the periphery under particular conditions of antigenic stimulation. [5][6][7] Although T reg cells were originally identified for their ability to prevent organ-specific autoimmune disease in mice, T reg cells have also been shown to suppress tumor-specific T-cell immunity [8][9][10][11][12] and thereby contribute to the progression of human tumors. 9,10,13,14 Expression of transcriptional factor forkhead box P3 (Foxp3) has been demonstrated to be crucial to the development and function of T reg cells. [15][16][17] Ectopic expression of Foxp3 in CD4 ϩ CD25 Ϫ naive T cells by retroviral gene transfer can convert them to natural T reg -like cells functionally and phenotypically.Transgenic mice lacking Foxp3 lack T cells with regulatory function and have dysregulated T-cell proliferation, resulting in a severe autoimmune disease. These results demonstrate that expression of Foxp3 is important for the function of T reg cells. Although T reg cells express high levels of Foxp3, Foxp3 expression can also be induced in CD4 ϩ CD25 Ϫ T cells by activation with corticosteroids, estrogen, and transforming growth factor-␤ (TGF-␤). [5][6][7] Although CD4 ϩ CD25 Ϫ T cells expressing Foxp3 have been recently reported in aging mice, 18 it is currently unclear whether CD4 ϩ CD25 Ϫ Foxp3 ϩ T cells are present in human tissue and what their significance may be.Similar to other types of tumors, lymphoma B cells are able to induce immune cell anergy in murine models. [19][20][21] In mice inoculated with lymphoma B-cell line A20, tumor antigen-specific CD4 ϩ T cells displayed a diminished response to peptide antigen in vitro and were unable to be primed in vivo. 19 In vivo disruption of tolerogenic cross-presentation mechanisms by disabling bonemarrow-derived APCs resulted in effective T-cell ac...

A variety of nonmalignant cells present in the tumor microenvironment promotes tumorigenesis by stimulating tumor cell growth and metastasis or suppressing host immunity. The role of such stromal cells in T-cell lymphoproliferative disorders is incompletely understood. Monocyte-derived cells (MDCs), including professional antigen-presenting cells such as dendritic cells (DCs), play a central role in T-cell biology. Here, we provide evidence that monocytes promote the survival of malignant T cells and demonstrate that MDCs are abundant within the tumor microenvironment of T cell-derived lymphomas. Malignant T cells were observed to remain viable during in vitro culture with autologous monocytes, but cell death was significantly increased after monocyte depletion. Furthermore, monocytes prevent the induction of cell death in T-cell lymphoma lines in response to either serum starvation or doxo-rubicin, and promote the engraftment of these cells in nonobese diabetic/severe combined immunodeficient mice. Mono-cytes are actively recruited to the tumor microenvironment by CCL5 (RANTES), where their differentiation into mature DCs is impaired by tumor-derived interleukin-10. Collectively, the data presented demonstrate a previously unde-scribed role for monocytes in T-cell lym-phoproliferative disorders. (Blood. 2009;

The underlying mechanisms by which tumor cells are resistant to CTL-mediated apoptosis are not clear. Using a human model of B-cell non-Hodgkin's lymphoma (B-cell NHL), we show that intratumoral T reg cells inhibit the proliferation and granule production of activated autologous infiltrating CD8 + T cells. Our results also show that degranulation and subsequent cytotoxic activity of infiltrating CD8 + T cells exposed to lymphoma B cells is completely attenuated by the presence of intratumoral T reg cells. Furthermore, we show that increased numbers of intratumoral T reg cells correlates with the number of CD8 + T cells in biopsy specimens from patients with B-cell NHL, supporting the in vitro findings that intratumoral T reg cells inhibit proliferation of infiltrating CD8 + T cells. Taken together, these data indicate that human lymphoma B cells are sensitive to autologous CTL-mediated cell death but are protected by the inhibitory function of intratumoral T reg cells.

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...

A BAFF receptor mutation associated with non-Hodgkin lymphoma provides new insight into the proximal players of normal BAFF-R signaling.