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

Authors' Affiliations: ¹ Department of Pathology, Hospital de Tortosa Verge de la Cinta, Tortosa, Spain and ² Department of Pathology, M. D. Anderson Internacional, Madrid, Spain

Requests for reprints: Tomás Álvaro, Department of Pathology, Hospital de Tortosa Verge de la Cinta, C/ Esplanetes n° 14, 43500 Tortosa, Spain. Phone: 34-977-519104; Fax: 34-977-519104; E-mail: talvaro.htvc.ics{at}gencat.net.

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-B) 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 G₁-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 1 and 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.