Tumor-Infiltrated Immune Response Correlates with Alterations in the Apoptotic and Cell Cycle Pathways in Hodgkin and Reed-Sternberg Cells

Abstract

Purpose: To analyze tumor-microenvironment relationships in Hodgkin lymphoma (HL) as potential determinants in the decision-making process related to the alterations in cell cycle and apoptotic pathways of Hodgkin/Reed-Sternberg (H/RS) cells. Experimental Design: Based on a cohort of 257 classic HL patients, we carried out a global descriptive correlational analysis and logistic regression study to identify tumor-infiltrated immune cell rate in HL that could be interconnected with genes involved in the regulation of apoptotic/proliferative pathways in H/RS cells. Results: Our results reveal the existence of a connection between the reactive microenvironment and molecular changes in apoptotic/proliferative pathways in H/RS cells. A lesser incidence of infiltrated cytotoxic cells in the tumor (CD8 + T lymphocytes, CD57 + natural killer, and granzyme B + cells) was associated with overexpression of antiapoptotic proteins (Bcl-X L , survivin, caspase-3, and nuclear factor-nB) in tumoral cells. Increased incidence of general infiltrated immune cells, such as CD4 + T lymphocytes, CD57 + natural killer cells, activated CTL, and dendritic cells, in the microenvironment of the tumor was associated with increased growth fraction of tumoral cells, including G 1 -S checkpoint (cyclin D and cyclin E) and tumor suppressor pathways (p16 and SKP2), and with the presence of EBV (signal transducers and activators of transcription 1and 3 expression; STAT1/STAT3). Conclusions: A lower level of cytotoxic cells correlated with an increase of antiapoptotic mechanisms in H/RS cells, whereas the global infiltrated immune population correlated with the growth fraction of the tumor. Our collective data suggest a causal relationship between infiltrated immune response and concurrent changes of the different proliferative checkpoints, tumor suppressor, and apoptotic pathways of H/RS cells in HL.

Positron emission tomography scanning: a new paradigm for the management of Hodgkin's lymphoma

“…5 These latter cells are recruited by chemokines produced by the HRS cells and induce expression of anti-apoptotic proteins in HRS cells and their immortalization via a paracrine loop. 6 The chemokines responsible for recruitment of cells to the microenvironment, thymus and activation-regulated chemokines (TARC-CCL7) and macrophage-derived chemokines (MDC), selectively attract CCR4-expressing cell subsets, including eosinophils, histiocytes, macrophages, plasma cells, and Th2 and Treg lymphocytes, which are all readily detected at tumor sites. There is convincing evidence that forced expression of CCR4 by these various subsets of cells provides the cells with the capacity to migrate along a TARC gradient, so that the function of the CCR4 receptor is not restricted to the subset of T cells on which it is physiologically expressed.…”

High tumour-associated macrophages infiltration is correlated with poor survival outcome in classical Hodgkin’s lymphoma

“…[11,19,27,28] cHL microenvironment is modulated by cytokines and chemokines produced by HRS cells. [29] The non-neoplastic cells are suggested to have a strong contribution to the biological behaviour of HL as well as prediction of treatment outcome.…”

Resveratrol down-regulates survivin and induces apoptosis in human multidrug-resistant SPC-A-1/CDDP cells

“…Survivin is a member of the inhibitor of apoptosis protein (IAP) family that inhibits apoptosis and regulates cell division (32). Survivin has been implicated in both the control of cell division and the inhibition of apoptosis (33). Specifically, its anti-apoptotic function seems to be related to the ability to directly or indirectly inhibit caspases.…”