Targeting the Adenosinergic Axis in Chronic Lymphocytic Leukemia: A Way to Disrupt the Tumor Niche?

Targeting adenosine triphosphate (ATP) metabolism and adenosinergic signaling in cancer is gaining momentum, as increasing evidence is showing their relevance in tumor immunology and biology. Chronic lymphocytic leukemia (CLL) results from the expansion of a population of mature B cells that progressively occupies the bone marrow (BM), the blood, and peripheral lymphoid organs. Notwithstanding significant progress in the treatment of these patients, the cure remains an unmet clinical need, suggesting that novel drugs or drug combinations are needed. A unique feature of CLL is its reliance on micro-environmental signals for proliferation and cell survival. We and others have shown that the lymphoid niche, an area of intense interactions between leukemic and bystander non-tumor cells, is a typically hypoxic environment. Here adenosine is generated by leukemic cells, as well as by cells of myeloid origin, acting through autocrine and paracrine mechanisms, ultimately affecting tumor growth, limiting drug responses, and skewing the immune cells towards a tolerant phenotype. Hence, understanding the mechanisms through which this complex network of enzymes, receptors, and metabolites functions in CLL, will pave the way to the use of pharmacological agents targeting the system, which, in combination with drugs targeting leukemic cells, may get us one step closer to curing these patients.