Molecular and Microenvironmental Basis of Immunodysfunction in CLL

Context Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease.1 Effectors of the innate and the adaptive immune response show marked dysfunction and skewing toward the generation of a tolerant environment that favors disease expansion. Major deregulations have been described in the T lymphocyte compartment, with inhibition of CD8+ cytotoxic and CD4+ activated effector T cells replaced by exhausted and tolerogenic subsets. Likewise, differentiation of monocytes toward a suppressive M2-like phenotype is induced at the expense of pro-inflammatory subpopulations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell-cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis.2