T Cells in Chronic Lymphocytic Leukemia: A Two-Edged Sword

Chronic lymphocytic leukemia (CLL) is a malignancy of mature, antigen-experienced B lymphocytes. Despite great progress recently achieved in the management of CLL, the disease remains incurable, underscoring the need for further investigation into the underlying pathophysiology. Microenvironmental crosstalk has an established role in CLL pathogenesis and progression. Indeed, the malignant CLL cells are strongly dependent on interactions with other immune and non-immune cell populations that shape a highly orchestrated network, the tumor microenvironment (TME). The composition of the TME, as well as the bidirectional interactions between the malignant clone and the microenvironmental elements have been linked to disease heterogeneity. Mounting evidence implicates T cells present in the TME in the natural history of the CLL as well as in the establishment of certain CLL hallmarks e.g. tumor evasion and immune suppression. CLL is characterized by restrictions in the T cell receptor gene repertoire, T cell oligoclonal expansions, as well as shared T cell receptor clonotypes amongst patients, strongly alluding to selection by restricted antigenic elements of as yet undisclosed identity. Further, the T cells in CLL exhibit a distinctive phenotype with features of exhaustion likely as a result of chronic antigenic stimulation. This might be relevant to the fact that, despite increased numbers of oligoclonal T cells in the periphery, these cells are incapable of mounting effective anti-tumor immune responses, a feature perhaps also linked with the elevated numbers of T regulatory subpopulations. Alterations of T cell gene expression profile are associated with defects in both the cytoskeleton and immune synapse formation, and are generally induced by direct contact with the malignant clone. That said, these abnormalities appear to be reversible, which is why therapies targeting the T cell compartment represent a reasonable therapeutic option in CLL. Indeed, novel strategies, including CAR T cell immunotherapy, immune checkpoint blockade and immunomodulation, have come to the spotlight in an attempt to restore the functionality of T cells and enhance targeted cytotoxic activity against the malignant clone.

Automated summary

Chronic lymphocytic leukemia remains incurable despite recent progress in management, highlighting the importance of further investigating the underlying pathophysiology. The interactions between malignant CLL cells and the tumor microenvironment play a crucial role in disease progression, with T cell abnormalities and potential therapeutic targets being a key focus in enhancing targeted cytotoxic activity against the malignant clone.