Tumor-infiltrated immune response correlates with alterations in the apoptotic and cell cycle pathways in Hodgkin and Reed-Sternberg cells.
OBJECTIVE
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.


METHODS
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-kappaB) 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 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.
Alvaro
Tomás
T
Department of Pathology, Hospital de Tortosa Verge de la Cinta, Tortosa, Spain. talvaro.htvc.ics@gencat.net
Lejeune
Marylène
M
García
Juan F
JF
Salvadó
Ma Teresa
MT
López
Carlos
C
Bosch
Ramón
R
Jaén
Joaquín
J
Escrivá
Patricia
P
Pons
Lluis E
LE
D017209:Apoptosis; D002453:Cell Cycle; D003713:Dendritic Cells / Q000473:pathology; D006689:Hodgkin Disease / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007694:Killer Cells, Natural / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D016539:Reed-Sternberg Cells / Q000276:immunology / Q000473:pathology*; D012044:Regression Analysis; D013601:T-Lymphocytes / Q000473:pathology