RESUMO
Abcc3, a member of the ATP-binding cassette transporter superfamily, plays a role in multidrug resistance. Here, we found that Abcc3 is highly expressed in blood-derived NK cells but not in CD8(+) T cells. In GL261 glioma-bearing mice treated with the alkylating agent temozolomide (TMZ) for 5 d, an early increased frequency of NK cells was observed. We also found that Abcc3 is strongly upregulated and functionally active in NK cells from mice treated with TMZ compared to controls. We demonstrate that Abcc3 is critical for NK cell survival during TMZ administration; more importantly, Akt, involved in lymphocyte survival, is phosphorylated only in NK cells expressing Abcc3. The resistance of NK cells to chemotherapy was accompanied by increased migration and homing in the brain at early time points. Cytotoxicity, evaluated by IFNγ production and specific lytic activity against GL261 cells, increased peripherally in the later phases, after conclusion of TMZ treatment. Intra-tumor increase of the NK effector subset as well as in IFNγ, granzymes and perforin-1 expression, were found early and persisted over time, correlating with a profound modulation on glioma microenvironment induced by TMZ. Our findings reveal an important involvement of Abcc3 in NK cell resistance to chemotherapy and have important clinical implications for patients treated with chemo-immunotherapy.
RESUMO
Glioblastoma (GBM) is the most common and aggressive primary brain tumor. To better understand how GBM evolves, we analyzed longitudinal genomic and transcriptomic data from 114 patients. The analysis shows a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern, together with estimates of evolutionary rate, suggests that relapse-associated clones typically existed years before diagnosis. Fifteen percent of tumors present hypermutation at relapse in highly expressed genes, with a clear mutational signature. We find that 11% of recurrence tumors harbor mutations in LTBP4, which encodes a protein binding to TGF-ß. Silencing LTBP4 in GBM cells leads to suppression of TGF-ß activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-ß pathway as a potential therapeutic target in GBM.