T Cell Defects and Immunotherapy in Chronic Lymphocytic Leukemia

SIMPLE SUMMARY: The treatment of chronic lymphocytic leukemia (CLL) is a rapidly evolving field; however, despite recent progress, CLL remains incurable. Different types of immunotherapy have emerged as therapeutic options for CLL, aiming to boost anti-tumor immune responses; that said, despite initial promising results, not all patients benefit from immunotherapy. Relevant to this, the tumor microenvironment (TME) in CLL has been proposed to suppress effective immune responses while also promoting tumor growth, hence impacting on the response to immunotherapy as well. T cells, in particular, are severely dysfunctional in CLL and cannot mount effective immune responses against the malignant cells. However, reinvigoration of their effector function is still a possibility under the proper manipulation and has been associated with tumor regression. In this contribution, we examine the current immunotherapeutic options for CLL in relation to well-characterized T cell defects, focusing on possible counteracts that enhance anti-tumor immunity through the available treatment modalities. ABSTRACT: In the past few years, independent studies have highlighted the relevance of the tumor microenvironment (TME) in cancer, revealing a great variety of TME-related predictive markers, as well as identifying novel therapeutic targets in the TME. Cancer immunotherapy targets different components of the immune system and the TME at large in order to reinforce effector mechanisms or relieve inhibitory and suppressive signaling. Currently, it constitutes a clinically validated treatment for many cancers, including chronic lymphocytic leukemia (CLL), an incurable malignancy of mature B lymphocytes with great dependency on microenvironmental signals. Although immunotherapy represents a promising therapeutic option with encouraging results in CLL, the dysfunctional T cell compartment remains a major obstacle in such approaches. In the scope of this review, we outline the current immunotherapeutic treatment options in CLL in the light of recent immunogenetic and functional evidence of T cell impairment. We also highlight possible approaches for overcoming T cell defects and invigorating potent anti-tumor immune responses that would enhance the efficacy of immunotherapy.