Expression of PIM kinases in Reed-Sternberg cells fosters immune privilege and tumor cell survival in Hodgkin lymphoma
PBN-AR
Instytucja
Instytut Hematologii i Transfuzjologii
Informacje podstawowe
Główny język publikacji
angielski
Czasopismo
BLOOD (50pkt w roku publikacji)
ISSN
0006-4971
EISSN
1528-0020
Wydawca
AMER SOC HEMATOLOGY
DOI
URL
Rok publikacji
2017
Numer zeszytu
130
Strony od-do
1418-1429
Numer tomu
12
Liczba arkuszy
Streszczenia
Język
angielski
Treść
Reed-Sternberg (RS) cells of classical Hodgkin lymphoma (cHL) express multiple immunoregulatory proteins that shape the cHL microenvironment and allow tumor cells to evade immune surveillance. Expression of certain immunoregulatory proteins is modulated by pro-survival transcription factors, such as NFκB and STATs. Since these factors also induce expression of the oncogenic PIM1/2/3 serine/threonine kinases, and since PIMs modulate transcriptional activity of NFκB and STATs, we hypothesized that these kinases support RS cell survival and foster their immune privilege. Herein, we investigated PIM1/2/3 expression in cHL and assessed their role in developing RS cell immune privilege and survival. PIM1/2/3 were ubiquitously expressed in primary and cultured RS cells and their expression was driven by JAK-STAT and NFκB activity. Genetic or chemical PIM inhibition with a newly developed pan-PIM inhibitor, SEL24-B489, induced RS cell apoptosis. PIM inhibition decreased cap-dependent protein translation, blocked JAK-STAT signaling, and markedly attenuated NFκB-dependent gene expression. In a cHL xenograft model, SEL24-B489 delayed tumor growth by 95.8% (p=0.0002). Furthermore, SEL24-B489 decreased the expression of multiple molecules engaged in developing the immunosuppressive microenvironment, including galectin-1 and PD-L1/2. In coculture experiments, T-cells incubated with SEL24-B489-treated RS cells exhibited higher expression of activation markers than T-cells co-incubated with control RS cells. Taken together, our data indicate that PIM kinases in cHL exhibit pleiotropic effects, orchestrating tumor immune escape and supporting RS cell survival. Inhibition of PIM kinases decreases RS cell viability and disrupts signaling circuits that link these cells with their niches. Thus, PIM kinases are promising therapeutic targets in cHL.
Cechy publikacji
original article
oryginalny artykuł naukowy
Inne
System-identifier
PX-59a3f8dfd5de3ddc80153f03
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