T-cell dysfunction by pseudohypoxia and autocrine purinergic signaling in chronic lymphocytic leukemia

Abstract

Acquired T-cell dysfunction is common in chronic B-cell malignancies. Given the strong connection between T-cell metabolism and function, we investigated metabolic alterations as the basis for T-cell dysfunction induced by malignant cells. Using B-cell malignant cell lines and human PBMCs, we first established a model which recapitulates major aspects of cancer-induced T-cell dysfunction. Cell lines derived from chronic lymphocytic leukemia (PGA-1, CII, Mec-1), but not from other B-cell malignancies, altered T-cell metabolome by generating a pseudohypoxic state. T cells were retained in aerobic glycolysis and were not able to switch to OXPHOS. Moreover, T cells produced immunosuppressive adenosine that negatively affected function by dampening activation, which could be restored by blocking of adenosine receptors. Subsequently, we uncovered a similar hypoxic-like signature in autologous T cells from primary CLL samples. Pseudohypoxia was reversible upon depletion of CLL cells ex vivo and, importantly, after in vivo reduction of the leukemic burden with combination therapy (Venetoclax and Obinutuzumab), restoring T-cell function. In conclusion, we uncover a pseudohypoxic program connected with T cell dysfunction in CLL. Modulation of hypoxia and the purinergic pathway might contribute to therapeutic restoration of T-cell function.

Glucose metabolism in B cell malignancies: a focus on glycolysis branching pathways

“…Besides, CLL T cells showed increased ROS levels and decreased expression of NRF2, which is a key antioxidant transcription factor that regulates, among others, the expression of key enzymes of the PPP and SBP [ 141 ]. In two follow‐up studies, we have shown that impaired OXPHOS [ 142 ], pseudohypoxia and adenosine signaling [ 143 ], contribute to at least part of the observed T cell dysfunction in CLL. Importantly, T cell dysfunction was reverted by depletion of CLL cells in vitro and in patients following treatment with venetoclax and obinutuzumab.…”